4-carboxybenzylamino derivatives as histone deacetylase inhibitors

ABSTRACT

The present invention relates to a novel class of 4-carboxybenzylamino derivatives. The 4-carboxybenzylamino compounds can be used to treat cancer. The 4-carboxybenzylamino compounds can also inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the 4-carboxybenzylamino derivatives and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the 4-carboxybenzylamino derivatives in vivo.

FIELD OF THE INVENTION

The present invention relates to a novel class of 4-carboxybenzylaminoderivatives. The 4-carboxybenzylamino compounds can be used to treatcancer. The 4-carboxybenzylamino compounds can also inhibit histonedeacetylase and are suitable for use in selectively inducing terminaldifferentiation, and arresting cell growth and/or apoptosis ofneoplastic cells, thereby inhibiting proliferation of such cells. Thus,the compounds of the present invention are useful in treating a patienthaving a tumor characterized by proliferation of neoplastic cells. Thecompounds of the invention can also be useful in the prevention andtreatment of TRX-mediated diseases, such as autoimmune, allergic andinflammatory diseases, and in the prevention and/or treatment ofdiseases of the central nervous system (CNS), such as neurodegenerativediseases.

BACKGROUND OF THE INVENTION

Compounds having a hydroxamic acid moiety have been shown to possessuseful biological activities. For example, many peptidyl compoundspossessing a hydroxamic acid moiety are known to inhibit matrixmetalloproteinases (MMPs), which are a family of zinc endopeptidases.The MMPs play a key role in both physiological and pathological tissuedegradation. Therefore, peptidyl compounds that have the ability toinhibit the action of MMPs show utility for the treatment or prophylaxisof conditions involving tissue breakdown and inflammation. Further,compounds having a hydroxamic acid moiety have been shown to inhibithistone deacetylases (HDACs), based at least in part on the zinc bindingproperty of the hydroxamic acid group.

The inhibition of HDACs can repress gene expression, includingexpression of genes related to tumor suppression. Inhibition of histonedeacetylase can lead to the histone deacetylase-mediated transcriptionalrepression of tumor suppressor genes. For example, inhibition of histonedeacetylase can provide a method for treating cancer, hematologicaldisorders, such as hematopoiesis, and genetic related metabolicdisorders. More specifically, transcriptional regulation is a majorevent in cell differentiation, proliferation, and apoptosis. There areseveral lines of evidence that histone acetylation and deacetylation aremechanisms by which transcriptional regulation in a cell is achieved(Grunstein, M., Nature, 389: 349-52 (1997)). These effects are thoughtto occur through changes in the structure of chromatin by altering theaffinity of histone proteins for coiled DNA in the nucleosome. There arefive types of histones that have been identified. Histones H2A, H2B, H3and H4 are found in the nucleosome, and H1 is a linker located betweennucleosomes. Each nucleosome contains two of each histone type withinits core, except for H1, which is present singly in the outer portion ofthe nucleosome structure. It is believed that when the histone proteinsare hypoacetylated, there is a greater affinity of the histone to theDNA phosphate backbone. This affinity causes DNA to be tightly bound tothe histone and renders the DNA inaccessible to transcriptionalregulatory elements and machinery.

The regulation of acetylated states occurs through the balance ofactivity between two enzyme complexes, histone acetyl transferase (HAT)and histone deacetylase (HDAC).

The hypoacetylated state is thought to inhibit transcription ofassociated DNA. This hypoacetylated state is catalyzed by largemultiprotein complexes that include HDAC enzymes. In particular, HDACshave been shown to catalyze the removal of acetyl groups from thechromatin core histones.

It has been shown in several instances that the disruption of HAT orHDAC activity is implicated in the development of a malignant phenotype.For instance, in acute promyelocytic leukemia, the oncoprotein producedby the fusion of PML and RAR alpha appears to suppress specific genetranscription through the recruitment of HDACs (Lin, R. J. et al.,Nature 391:811-14 (1998)). In this manner, the neoplastic cell is unableto complete differentiation and leads to excess proliferation of theleukemic cell line.

U.S. Pat. Nos. 5,369,108, 5,932,616, 5,700,811, 6,087,367 and 6,511,990,disclose hydroxamic acid derivatives useful for selectively inducingterminal differentiation, cell growth arrest or apoptosis of neoplasticcells. In addition to their biological activity as antitumor agents,these hydroxamic acid derivatives have recently been identified asuseful for treating or preventing a wide variety of thioredoxin(TRX)-mediated diseases and conditions, such as inflammatory diseases,allergic diseases, autoimmune diseases, diseases associated withoxidative stress or diseases characterized by cellularhyperproliferation (U.S. Application 2003/0235588). Further, thesehydroxamic acid derivatives have been identified as useful for treatingdiseases of the central nervous system (CNS) such as neurodegenerativediseases and for treating brain cancer (See, U.S. Application2004/0087657).

The inhibition of HDAC by the hydroxamic acid containing compoundsuberoylanilide hydroxamic acid (SAHA) disclosed in the above referencedU.S. patents, is thought to occur through direct interaction with thecatalytic site of the enzyme as demonstrated by X-ray crystallographystudies (Finnin, M. S. et al., Nature 401:188-193 (1999)). The result ofHDAC inhibition is not believed to have a generalized effect on thegenome, but rather, only affects a small subset of the genome (Van Lint,C. et al., Gene Expression 5:245-53 (1996)). Evidence provided by DNAmicroarrays using malignant cell lines cultured with a HDAC inhibitorshows that there are a finite (1-2%) number of genes whose products arealtered. For example, cells treated in culture with HDAC inhibitors showa consistent induction of the cyclin-dependent kinase inhibitor p21(Archer, S. Shufen, M. Shei, A., Hodin, R. PNAS 95:6791-96 (1998)). Thisprotein plays an important role in cell cycle arrest. HDAC inhibitorsare thought to increase the rate of transcription of p21 by propagatingthe hyperacetylated state of histones in the region of the p21 gene,thereby making the gene accessible to transcriptional machinery. Geneswhose expression is not affected by HDAC inhibitors do not displaychanges in the acetylation of regional associated histones (Dressel, U.et al., Anticancer Research 20(2A):1017-22 (2000)).

Further, hydroxamic acid derivatives such as SAHA have the ability toinduce tumor cell growth arrest, differentiation and/or apoptosis(Richon et al., Proc. Natl. Acad. Sci. USA, 93:5705-5708 (1996)). Thesecompounds are targeted towards mechanisms inherent to the ability of aneoplastic cell to become malignant, as they do not appear to havetoxicity in doses effective for inhibition of tumor growth in animals(Cohen, L. A. et al., Anticancer Research 19:4999-5006 (1999)).

In view of the wide variety of applications for compounds containinghydroxamic acid moieties, the development of new inhibitors havingimproved properties, for example, increased potency or increasedbioavailability is highly desirable.

SUMMARY OF THE INVENTION

The present invention relates to a novel class of 4-carboxybenzylaminoderivatives. The 4-carboxybenzylamino compounds can be used to treatcancer. The 4-carboxybenzylamino compounds can also inhibit histonedeacetylase and are suitable for use in selectively inducing terminaldifferentiation, and arresting cell growth and/or apoptosis ofneoplastic cells, thereby inhibiting proliferation of such cells. Thus,the compounds of the present invention are useful in treating a patienthaving a tumor characterized by proliferation of neoplastic cells. Thecompounds of the invention may also be useful in the prevention andtreatment of TRX-mediated diseases, such as autoimmune, allergic andinflammatory diseases, and in the prevention and/or treatment ofdiseases of the central nervous system (CNS), such as neurodegenerativediseases. The present invention further provides pharmaceuticalcompositions comprising the 4-carboxybenzylamino derivatives, and safe,dosing regimens of these pharmaceutical compositions, which are easy tofollow, and which result in a therapeutically effective amount of the4-carboxybenzylamino derivatives in vivo.

It has been unexpectedly discovered that certain 4-carboxybenzylaminoderivatives show improved activity as histone deacetylase (HDAC)inhibitors and/or attenuated off-target activity.

The present invention thus relates to compounds represented by Formula Iand pharmaceutically acceptable salts, solvates and hydrates thereof, asdetailed herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel class of 4-carboxybenzylaminoderivatives. In one embodiment, the 4-carboxybenzylamino derivatives caninhibit histone deacetylase and are suitable for use in selectivelyinducing terminal differentiation, and arresting cell growth and/orapoptosis of neoplastic cells, thereby inhibiting proliferation of suchcells. Thus, the compounds of the present invention are useful intreating cancer in a subject. The compounds of the invention may also beuseful in the prevention and treatment of TRX-mediated diseases, such asautoimmune, allergic and inflammatory diseases, and in the preventionand/or treatment of diseases of the central nervous system (CNS), suchas neurodegenerative diseases.

It has been unexpectedly and surprisingly discovered that certain4-carboxybenzylamino derivatives, show improved activity as histonedeacetylase (HDAC) inhibitors and/or attenuated off-target activity.

Compounds

The invention provides a compound represented by the followingstructural Formula:

wherein Cy is aryl or heteroaryl, optionally substituted with halo,methyl, methoxy, halomethyl, amino, hydroxyl, C(O)OCH₃ or C(O)NHCH₃;

R¹ and R² are independently selected from H, OH, halo, NH₂, C₁-C₄ alkyl,C₁-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄ alkoxy, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocyclic or substituted or unsubstituted aryl;

R³ is independently selected from H, OH, NH₂, nitro, CN, amide,carboxyl, C₁-C₇ alkoxy, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇haloalkyloxy, C₁-C₇ hydroxyalkyl, C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—,C₁-C₇ alkyl-C(═O)—, C₁-C₇ alkynyl, halo, hydroxyalkoxy, C₁-C₇alkyl-NHSO₂—, C₁-C₇ alkyl-SO₂NH—, C₁-C₇ alkylsulfonyl, C₁-C₇ alkylaminoor di(C₁-C₇)alkylamino;

R⁴ is selected from —NR⁶R⁷,

R⁵ is independently selected from H, OH, NH₂, nitro, CN, amide,carboxyl, C₁-C₇ alkoxy, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇haloalkyloxy, C₁-C₇ hydroxyalkyl, C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—,C₁-C₇ alkyl-C(═O)—, C₁-C₇ alkynyl, halo, hydroxyalkoxy, C₁-C₇alkyl-NHSO₂—, C₁-C₇ alkyl-SO₂NH—, C₁-C₇ alkylsulfonyl, C₁-C₇ alkylaminoor di(C₁-C₇)alkylamino;

R⁶ is independently selected from H, C₁-C₄ alkyl or C(O)R⁹;

R⁷ is selected from H, —(CR^(a) ₂)_(v)O(CR^(a) ₂)_(q)R¹², —(CR^(a)₂)_(s)C(O)(CR^(a) ₂)_(q)R¹³, —(CR^(a) ₂)_(s)C(O)O(CR^(a) ₂)_(q)R¹²,—(CR^(a) ₂)_(s)C(O)NR¹¹, —(CR^(a) ₂)_(q)R¹⁰, —(CR^(a) ₂)_(s)SO₂NR¹¹,—(CR^(a) ₂)_(v)NR¹¹;

R⁸ is independently selected from H, C₁-C₄ alkyl, N(R⁶)₂, —(CR^(a)₂)_(q)R¹² or when m is at least 2, two adjacent R⁸ form an aryl ring;

R⁹ is selected from H or C₁-C₄ alkyl;

R¹⁰ is selected from H, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, pyrimidinyl, substitutedor unsubstituted pyridyl, substituted or unsubstituted thienyl,substituted or unsubstituted pyrazolyl, substituted or unsubstitutedthiazolyl, or phenyl;

R¹¹ is independently selected from H, substituted or unsubstituted C₁-C₇alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclic, substituted or unsubstituted heteroaryl,substituted or unsubstituted aryl, substituted or unsubstituted C₃-C₈alkylcycloalkyl, substituted or unsubstituted alkylheterocyclic,substituted or unsubstituted alkylheteroaryl or substituted orunsubstituted alkylaryl;

R¹² is independently selected from H, substituted or unsubstituted C₁-C₇alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclic orsubstituted or unsubstituted aryl;

R¹³ is selected from H, substituted or unsubstituted C₁-C₇ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclic orsubstituted or unsubstituted aryl;

R^(a) is independently selected from H or C₁-C₄ alkyl;

Ring B is aryl or heteroaryl;

m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

p is 1, 2, 3 or 4;

s and q are independently 0, 1, 2, 3, or 4;

t and v are independently 1, 2, 3 or 4;

L¹ is (CH₂)_(r), ethenyl or cyclopropyl, wherein r is 0, 1 or 2;

X is OH, SH or NH₂;

With the proviso that when R⁵ is H, X is NH₂ or OH, L¹ is a bond, R³ isH, R¹ and R² are H, R⁴ is

and Ring B is phenyl, then Cy is not

or a stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment of the invention, the compounds of the presentinvention are represented by Formula II:

wherein all substituents are defined above.

In another embodiment of the invention under Formula I or II, wherein Cyis aryl or heteroaryl, optionally substituted with halo, methyl,methoxy, amino, hydroxyl or halomethyl;

R¹ and R² are independently selected from H, OH, halo, NH₂, C₁-C₄ alkyl,or C₁-C₁₀ alkoxy;

R³ is independently selected from H, OH, NH₂, nitro, CN, amide,carboxyl, C₁-C₇ alkoxy, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇haloalkyloxy, C₁-C₇ hydroxyalkyl, C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—,C₁-C₇ alkyl-C(═O)—, C₁-C₇ alkynyl, halo, hydroxyalkoxy, C₁-C₇alkyl-NHSO₂—, C₁-C₇ alkyl-SO₂NH—, C₁-C₇ alkylsulfonyl, C₁-C₇ alkylaminoor di(C₁-C₇)alkylamino;

R⁴ is selected from —NR⁶R⁷,

R⁵ is independently selected from H, OH, NH₂, nitro, CN, amide,carboxyl, C₁-C₂ alkoxy, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂haloalkyloxy, C₁-C₂ hydroxyalkyl, C₁-C₂ alkenyl, C₁-C₂ alkyl-C(═O)O—,C₁-C₂alkyl-C(═O)—, C₁-C₂ alkynyl, halo, hydroxyalkoxy, C₁-C₂alkyl-NHSO₂—, C₁-C₂ alkyl-SO₂NH—, C₁-C₂ alkylsulfonyl, C₁-C₂ alkylaminoor di(C₁-C₂)alkylamino;

R⁶ is independently selected from H or C₁-C₄ alkyl;

R⁷ is selected from H, —(CR^(a) ₂)_(v)O(CR^(a) ₂)_(q)R¹², —C(O)(CR^(a)₂)_(q)R¹³, —(CR^(a) ₂)_(s)C(O)NR¹¹ or —(CR^(a) ₂)_(v)NR¹¹;

R⁸ is independently selected from H, C₁-C₄ alkyl, N(R⁶)₂, —(CR^(a)₂)_(q)R¹² or when m is at least 2, two adjacent R⁸ form an aryl ring;

R⁹ is selected from H or C₁-C₄ alkyl;

R¹¹ is independently selected from H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,heteroaryl, aryl, heterocyclic, C₃-C₆ alkylcycloalkyl, alkylheteroaryl,alkylaryl or alkylheterocyclic, wherein the alkyl, cycloalkyl,heteroaryl, heterocyclic, aryl, alkylcycloalkyl, alkylheteroaryl,alkylheterocyclic, or alkylaryl is optionally substituted with aryl,heteroaryl, halo, C₁-C₄ alkyl, N(R⁶)₂, OH, C₁-C₄ alkoxy or C₁-C₄haloalkyl;

R¹² is selected from H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, heteroaryl, arylor heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclicor aryl is optionally substituted with aryl, heteroaryl, halo, C₁-C₄alkyl, N(R⁶)₂, OH, C₁-C₄ alkoxy or C₁-C₄ haloalkyl;

R¹³ is selected from H, C₂-C₇ alkyl, C₃-C₈ cycloalkyl, heteroaryl, oraryl, wherein the cycloalkyl, heteroaryl or aryl is optionallysubstituted with aryl, heteroaryl, halo, C₁-C₄ alkyl, N(R⁶)₂, OH, C₁-C₄alkoxy or C₁-C₄ haloalkyl;

R^(a) is independently selected from H or C₁-C₄ alkyl;

Ring B is aryl or heteroaryl;

m is 1, 2, 3, 4, 5, 6, 7, or 8;

p is 1, 2, 3 or 4;

s and q are independently 0, 1, 2, 3, or 4;

t and v are independently 1, 2, 3 or 4;

L¹ is (CH₂)_(r), ethenyl or cyclopropyl, wherein r is 0, 1 or 2;

X is OH or NH₂;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment of the invention under Formula I or II,

Cy is

R¹ and R² are H;

R³ is H;

R⁴ is —NR⁶R⁷;

R⁵ is H;

R⁶ is selected from H or C₁-C₄ alkyl;

R⁷ is —C(O)(CR^(a) ₂)_(q)R¹³;

R¹³ is selected from H, C₂-C₄ alkyl, cycloalkyl, aryl or heteroaryl;

R¹⁷ and R²¹ are independently selected from hydrogen or fluoro;

R¹⁸, R¹⁹ or R²⁰ are independently selected from hydrogen, halo, methyl,methoxy or halomethyl;

R²², R²³ and R²⁴ are independently selected from hydrogen, methyl,amino, hydroxyl, and halo;

R^(a) is independently H or C₁-C₄ alkyl;

Ring B is aryl or heteroaryl;

q is independently 0, 1 or 2;

L¹ is a bond;

X is NH₂;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment of the invention under Formula I or II, Cy isphenyl or thienyl. In a further embodiment, Ring B is phenyl. In anotherembodiment, Ring B is

In a further embodiment, Cy is

R¹ and R² are H;

R³ is H;

R⁴ is —NR⁶R⁷;

R⁵ is H;

R⁶ is selected from H or C₁-C₄ alkyl;

R⁷ is —C(O)O(CR^(a) ₂)_(q)R¹²;

R¹² is selected from H, C₁-C₄ alkyl, cycloalkyl, aryl, or heteroaryl;

R¹⁷ and R²¹ are independently selected from hydrogen or fluoro;

R¹⁸, R¹⁹ or R²⁰ are independently selected from hydrogen, halo, methyl,methoxy or halomethyl;

R²², R²³ and R²⁴ are independently selected from hydrogen, methyl,amino, hydroxyl or halo;

R^(a) is independently H or C₁-C₄ alkyl;

Ring B is aryl or heteroaryl;

q is independently 0, 1 or 2;

L¹ is a bond;

X is NH₂;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment of the invention under Formula I or II, Cy isphenyl. In a further embodiment, Ring B is phenyl. In anotherembodiment, Ring B is

In a further embodiment, Cy is

Specific embodiments depicting non-limiting Examples of the4-carboxybenzylamino derivatives of the above Formulas are provided inTables 1 to 10 in the Experimental Section hereinbelow.

Specific examples of the compounds of the instant invention include:

-   pyridin-3-ylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   methyl    4′-amino-3′-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]biphenyl-4-carboxylate;-   pyridin-3-ylmethyl[(4-{[(2-amino-5-pyridin-3-ylphenyl)amino]carbonyl}phenyl)methyl]carbamate;-   pyridin-3-ylmethyl    {[4-({[2-amino-5-(3-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;-   pyridin-3-ylmethyl[(4-{[(4-hydroxybiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   pyridin-3-ylmethyl[(4-{[(2-hydroxy-5-pyridin-3-ylphenyl)amino]carbonyl}phenyl)methyl]carbamate;-   1,1-dimethylethyl[(4-{[(4-hydroxybiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   4-(aminomethyl)-N-(4-hydroxybiphenyl-3-yl)benzamide;-   methyl    [(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   ethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   1-methylethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   propyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   2-methylpropyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   phenyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   phenylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   ethyl    {[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;-   methyl    {[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;-   1-methylethyl    {[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;-   propyl    {[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;-   2-methylpropyl    {[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;-   phenyl    {[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;-   phenylmethyl    {[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;-   4-[(acetylamino)methyl]-N-(4-aminobiphenyl-3-yl)benzamide;-   N-(4-aminobiphenyl-3-yl)-4-[(propanoylamino)methyl]benzamide;-   N-(4-aminobiphenyl-3-yl)-4-[(butanoylamino)methyl]benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(cyclopropylcarbonyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(2-methylpropanoyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(3-methylbutanoyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(cyclobutylcarbonyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(3-phenylpropanoyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(cyclohexylcarbonyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(cyclopentylcarbonyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(phenylacetyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(phenylcarbonyl)amino]methyl}benzamide;-   4-[(acetylamino)methyl]-N-[2-amino-5-(2-thienyl)phenyl]benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-[(propanoylamino)methyl]benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-[(butanoylamino)methyl]benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(cyclopropylcarbonyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(2-methylpropanoyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(3-methylbutanoyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(cyclobutylcarbonyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(3-phenylpropanoyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(cyclohexylcarbonyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(cyclopentylcarbonyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(phenylacetyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(phenylcarbonyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(pyridin-2-ylacetyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(pyridin-3-ylacetyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(pyridin-4-ylacetyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(3-pyridin-3-ylpropanoyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(pyridin-2-ylacetyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(pyridin-4-ylacetyl)amino]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(3-pyridin-3-ylpropanoyl)amino]methyl}benzamide;-   (2S)—N-[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]pyrrolidine-2-carboxamide;-   (2S)—N-(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}benzyl)pyrrolidine-2-carboxamide;-   pyridin-2-ylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;-   N-[2-amino-5-(2-thienyl)phenyl]-4-({[(dimethylamino)sulfonyl]amino}methyl)benzamide;-   N-(4-amino-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide;-   N-(4-amino-3-biphenylyl)-4-{[methyl(4-pyridinyl)amino]methyl}benzamide;-   N-(4-amino-3-biphenylyl)-4-({[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]amino}methyl)benzamide;-   N-(4-amino-3-biphenylyl)-4-({methyl[3-(methylamino)propyl]amino}methyl)benzamide;-   N-(4-amino-3-biphenylyl)-4-[(isobutylamino)methyl]benzamide;-   N-(4-amino-3-biphenylyl)-4-{[(2-methoxy-1-methylethyl)amino]methyl}benzamide;-   N-(4-amino-2′-fluoro-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide;-   N-(4-amino-3′-fluoro-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide;-   N-[2-amino-5-(4-methyl-2-thienyl)phenyl]-4-[(4-pyridinylamino)methyl]benzamide;-   N-[2-amino-5-(4-methyl-3-thienyl)phenyl]-4-[(4-pyridinylamino)methyl]benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[(2-phenylethyl)amino]methyl}benzamide;-   4-({[2-(4-bromophenyl)ethyl]amino}methyl)-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-[(isobutylamino)methyl]benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methyl]amino}methyl)benzamide;-   4-[(cyclopropylamino)methyl]-N-(4-hydroxy-3-biphenylyl)benzamide;-   4-(anilinomethyl)-N-(4-hydroxy-3-biphenylyl)benzamide;-   4-[(cyclopentylamino)methyl]-N-(4-hydroxy-3-biphenylyl)benzamide;-   4-{[(cyclopropylmethyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)benzamide;-   4-({[2-(dimethylamino)ethyl]amino}methyl)-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[(3-pyridinylmethyl)amino]methyl}benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({[3-(1-pyrrolidinyl)propyl]amino}methyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-(1-piperazinylmethyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-(4-morpholinylmethyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[(3-isopropoxypropyl)amino]methyl}benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-[(4-methyl-1-piperidinyl)methyl]benzamide;-   4-{[benzyl(methyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[(3-phenylpropyl)amino]methyl}benzamide;-   4-(3,4-dihydro-2(1H)-isoquinolinylmethyl)-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({[2-(isopropylamino)ethyl]amino}methyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[(3-methylbutyl)amino]methyl}benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[methyl(2-phenylethyl)amino]methyl}benzamide;-   4-{[ethyl(methyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;-   4-(1,3-dihydro-2H-isoindol-2-ylmethyl)-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[(2-phenoxyethyl)amino]methyl}benzamide;-   4-{[(2-anilinoethyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[(2-thienylmethyl)amino]methyl}benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({methyl[3-(methylamino)propyl]amino}methyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-[(4-methyl-1-piperazinyl)methyl]benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({methyl[2-(methylamino)ethyl]amino}methyl)benzamide;-   4-({[(1-ethyl-4-piperidinyl)methyl]amino}methyl)-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[methyl(4-pyridinyl)amino]methyl}benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({methyl[2-(4-pyridinyl)ethyl]amino}methyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({[2-(3-pyridinyl)ethyl]amino}methyl)benzamide;-   4-{[3-(dimethylamino)-1-pyrrolidinyl]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;-   4-{[(2-aminoethyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;-   4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-N-(4-hydroxy-3-biphenylyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({[3-(4-pyridinyl)propyl]amino}methyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({[(1-methyl-3-pyrrolidinyl)methyl]amino}methylbenzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({[2-(1H-pyrazol-1-yl)ethyl]amino}methyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[methyl(tetrahydro-3-furanyl)amino]methyl}benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[methyl(2-pyrazinylmethyl)amino]methyl}benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino}methyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-({methyl[(1-methyl-4-piperidinyl)methyl]amino}methyl)benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[2-(2-pyridinyl)-1-pyrrolidinyl]methyl}benzamide;-   N-(4-hydroxy-3-biphenylyl)-4-{[(3-methoxybenzyl)amino]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]methyl}benzamide;-   N-[2-amino-5-(2-thienyl)phenyl]-4-{[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]methyl}benzamide;-   N-(4-aminobiphenyl-3-yl)-4-{[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}benzamide;-   {[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]amino}acetic    acid;-   {[4-({[2-amino-5-(3-thienyl)phenyl]amino}carbonyl)benzyl]amino}acetic    acid; or-   4-({Acetyl[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)-N-[2-amino-5-(2-thienyl)phenyl]benzamide;    or the pharmaceutically acceptable salt or stereoisomer thereof.

CHEMICAL DEFINITIONS

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear or branched arrangement. For example, “C₁-C₁₀alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.

When used in the phrases “alkylaryl”, “alkylcycloalkyl” and“alkylheterocyclyl” the term “alkyl” refers to the alkyl portion of themoiety and does not describe the number of atoms in the aryl andheterocyclyl portion of the moiety. In an embodiment, if the number ofcarbon atoms is not specified, the “alkyl” of “alkylaryl”,“alkylcycloalkyl” and “alkylheterocyclyl” refers to C₁-C₁₂ alkyl and ina further embodiment, refers to C₁-C₆ alkyl.

The term “cycloalkyl” means a monocyclic saturated or unsaturatedaliphatic hydrocarbon group having the specified number of carbon atoms.The cycloalkyl is optionally bridged (i.e., forming a bicyclic moiety),for example with a methylene, ethylene or propylene bridge. Thecycloalkyl may be fused with an aryl group such as phenyl, and it isunderstood that the cycloalkyl substituent is attached via thecycloalkyl group. For example, “cycloalkyl” includes cyclopropyl,methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl,cyclohexyl, cyclopentenyl, cyclobutenyl and so on.

In an embodiment, if the number of carbon atoms is not specified,“alkyl” refers to C₁-C₁₂ alkyl and in a further embodiment, “alkyl”refers to C₁-C₆ alkyl. In an embodiment, if the number of carbon atomsis not specified, “cycloalkyl” refers to C₃-C₁₀ cycloalkyl and in afurther embodiment, “cycloalkyl” refers to C₃-C₇ cycloalkyl. In anembodiment, examples of “alkyl” include methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl and i-butyl.

The term “alkylene” means a hydrocarbon diradical group having thespecified number of carbon atoms. For example, “alkylene” includes—CH₂—, —CH₂CH₂— and the like. In an embodiment, if the number of carbonatoms is not specified, “alkylene” refers to C₁-C₁₂ alkylene and in afurther embodiment, “alkylene” refers to C₁-C₆ alkylene.

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight, branched or cyclic,containing from 2 to 10 carbon atoms and at least one carbon to carbondouble bond. Preferably one carbon to carbon double bond is present, andup to four non-aromatic carbon-carbon double bonds may be present. Thus,“C₂-C₆ alkenyl” means an alkenyl radical having from 2 to 6 carbonatoms. Alkenyl groups include ethenyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl. The straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

“Aryl” is intended to mean any stable monocyclic, bicyclic or tricycliccarbon ring of up to 7 atoms in each ring, wherein at least one ring isaromatic. Examples of such aryl elements include phenyl, naphthyl,tetrahydronaphthyl, indanyl and biphenyl. In cases where the arylsubstituent is bicyclic and one ring is non-aromatic, it is understoodthat attachment is via the aromatic ring.

In one embodiment, “aryl” is an aromatic ring of 6 to 14 carbons atoms,and includes a carbocyclic aromatic group fused with a 5- or 6-memberedcycloalkyl group such as indan. Examples of carbocyclic aromatic groupsinclude, but are not limited to, phenyl, naphthyl, e.g. 1-naphthyl and2-naphthyl; anthracenyl, e.g. 1-anthracenyl, 2-anthracenyl;phenanthrenyl; fluorenonyl, e.g. 9-fluorenonyl, indanyl and the like.

The term heteroaryl, as used herein, represents a stable monocyclic,bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein atleast one ring is aromatic and contains carbon and from 1 to 4heteroatoms selected from the group consisting of O, N and S. In anotherembodiment, the term heteroaryl refers to a monocyclic, bicyclic ortricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one tofour heteroatoms selected from O, N, or S. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

Heteroaryl groups within the scope of this definition include but arenot limited to acridinyl, carbazolyl, cinnolinyl, quinoxalinyl,pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl,pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrahydroquinoline. Additional examples of heteroaryl include, but arenot limited to pyridyl, e.g., 2-pyridyl (also referred to as α-pyridyl),3-pyridyl (also referred to as β-pyridyl) and 4-pyridyl (also referredto as (γ-pyridyl); thienyl, e.g., 2-thienyl and 3-thienyl; furanyl,e.g., 2-furanyl and 3-furanyl; pyrimidyl, e.g., 2-pyrimidyl and4-pyrimidyl; imidazolyl, e.g., 2-imidazolyl; pyranyl, e.g., 2-pyranyland 3-pyranyl; pyrazolyl, e.g., 4-pyrazolyl and 5-pyrazolyl; thiazolyl,e.g., 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; thiadiazolyl;isothiazolyl; oxazolyl, e.g., 2-oxazoyl, 4-oxazoyl and 5-oxazoyl;isoxazoyl; pyrrolyl; pyridazinyl; pyrazinyl and the like.

In an embodiment, “heteroaryl” may also include a “fused polycyclicaromatic”, which is a heteroaryl fused with one or more other heteroarylor nonaromatic heterocyclic ring. Examples include, quinolinyl andisoquinolinyl, e.g. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl,1-isoquinolinyl, 3-quinolinyl, 4-isoquinolinyl, 5-isoquinolinyl,6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl; benzofuranyl, e.g.2-benzofuranyl and 3-benzofuranyl; dibenzofuranyl, e.g.2,3-dihydrobenzofuranyl; dibenzothiophenyl; benzothienyl, e.g.2-benzothienyl and 3-benzothienyl; indolyl, e.g. 2-indolyl and3-indolyl; benzothiazolyl, e.g., 2-benzothiazolyl; benzooxazolyl, e.g.,2-benzooxazolyl; benzimidazolyl, e.g. 2-benzoimidazolyl; isoindolyl,e.g. 1-isoindolyl and 3-isoindolyl; benzotriazolyl; purinyl;thionaphthenyl, pyrazinyl and the like.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean monocyclic, spirocyclic, bicyclic or tricyclic ring of up to 7atoms in each ring, wherein each ring is aromatic or non-aromatic andcontains carbon and from 1 to 4 heteroatoms selected from the groupconsisting of O, N, P and S. A nonaromatic heterocycle may be fused withan aromatic aryl group such as phenyl or aromatic heterocycle.

“Heterocyclyl” therefore includes the above mentioned heteroaryls, aswell as dihydro and tetrahydro analogs thereof. Further examples of“heterocyclyl” include, but are not limited to the following:azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

In an embodiment, “heterocycle” (also referred to herein as“heterocyclyl”), is a monocyclic, spirocyclic, bicyclic or tricyclicsaturated or unsaturated ring of 5- to 14-ring atoms of carbon and fromone to four heteroatoms selected from O, N, S or P. Examples ofheterocyclic rings include, but are not limited to: pyrrolidinyl,piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl, dihydrofuranyl,tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, dihydroquinolinyl,tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl,dihydropyrazinyl, tetrahydropyrazinyl, dihydropyridyl, tetrahydropyridyland the like.

An “alkylaryl group” (arylalkyl) is an alkyl group substituted with anaromatic group, for example, a phenyl group. In one embodiment,alkylaryl group is a benzyl group. Suitable aromatic groups aredescribed herein and suitable alkyl groups are described herein.

An “alkylheteroaryl group” (heteroarylalkyl) is an alkyl groupsubstituted with a heteroaryl group. Suitable heteroaryl groups aredescribed herein and suitable alkyl groups are described herein.

An “alkylheterocyclyl” group” is an alkyl group substituted with aheterocyclyl group. Suitable heterocyclyl groups are described hereinand suitable alkyl groups are described herein. Suitable substituentsfor an alkylheterocyclyl group are described herein.

An “alkylcycloalkyl group” is an alkyl group substituted with acycloalkyl group. Suitable cycloalkyl groups are described herein andsuitable alkyl groups are described herein.

An “aryloxy group” is an aryl group that is attached to a compound viaan oxygen (e.g., phenoxy).

An “alkoxy group” (alkyloxy), as used herein, is a straight chain orbranched C₁-C₁₂ or cyclic C₃-C₁₂ alkyl group that is connected to acompound via an oxygen atom. Examples of alkoxy groups include but arenot limited to methoxy, ethoxy and propoxy.

An “arylalkoxy group” (arylalkyloxy) is an arylalkyl group that isattached to a compound via an oxygen on the alkyl portion of thearylalkyl (e.g., phenylmethoxy).

An “arylamino group” as used herein, is an aryl group that is attachedto a compound via a nitrogen.

An “alkylamino group” as used herein, is an alkyl group that is attachedto a compound via a nitrogen.

As used herein, an “arylalkylamino group” is an arylalkyl group that isattached to a compound via a nitrogen on the alkyl portion of thearylalkyl.

An “alkylsulfonyl group” as used herein, is an alkyl group that isattached to a compound via the sulfur of a sulfonyl group.

When a moiety is referred to as “unsubstituted” or not referred to as“substituted” or “optionally substituted”, it means that the moiety doesnot have any substituents. When a moiety is referred to as“substituted”, it denotes that any portion of the moiety that is knownto one skilled in the art as being available for substitution can besubstituted. The phrase “optionally substituted with one or moresubstituents” means, in one embodiment, one substituent, twosubstituents, three substituents, four substituents or fivesubstituents. For example, the substitutable group can be a hydrogenatom that is replaced with a group other than hydrogen (i.e., asubstituent group). Multiple substituent groups can be present. Whenmultiple substituents are present, the substituents can be the same ordifferent and substitution can be at any of the substitutable sites.Such means for substitution are well known in the art. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention, some examples of groups that are substituents are:alkyl, alkenyl or alkynyl groups (which can also be substituted, withone or more substituents), alkoxy groups (which can be substituted), ahalogen or halo group (F, Cl, Br, I), hydroxy, nitro, oxo, —CN, —COH,—COOH, amino, azido, N-alkylamino or N,N-dialkylamino (in which thealkyl groups can also be substituted), N-arylamino or N,N-diarylamino(in which the aryl groups can also be substituted), esters (—C(O)—OR,where R can be a group such as alkyl, aryl, etc., which can besubstituted), ureas (—NHC(O)—NHR, where R can be a group such as alkyl,aryl, etc., which can be substituted), carbamates (—NHC(O)—OR, where Rcan be a group such as alkyl, aryl, etc., which can be substituted),sulfonamides (—NHS(O)₂R, where R can be a group such as alkyl, aryl,etc., which can be substituted), alkylsulfonyl (which can besubstituted), aryl (which can be substituted), cycloalkyl (which can besubstituted) alkylaryl (which can be substituted), alkylheterocyclyl(which can be substituted), alkylcycloalkyl (which can be substituted),and aryloxy.

In one embodiment, Cy is phenyl, thienyl or pyridyl, optionallysubstituted with halo, methyl, methoxy, amino, hydroxyl or halomethyl.In one embodiment, Cy is

R¹⁷ and R²¹ are independently selected from hydrogen or fluoro;

R¹⁸, R¹⁹ or R²⁰ are independently selected from hydrogen, halo, methyl,methoxy or halomethyl;

R²², R²³ and R²⁴ are independently selected from hydrogen, methyl,amino, hydroxyl, and halo.

In another embodiment, Cy is phenyl or thienyl. In a further embodiment,Cy is phenyl.

In another embodiment, Cy is

In one embodiment, R¹ and R² are independently selected from H, OH,halo, NH₂, C₁-C₄ alkyl, or C₁-C₁₀ alkoxy. In another embodiment, R¹ andR² are H. In one embodiment, R¹ and R² are independently selected fromH, OH, halo, NH₂, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, heteroaryl, heterocyclic or aryl, wherein thecycloalkyl, heteroaryl, heterocyclic or aryl is optionally substitutedwith OH, NH₂, nitro, CN, amide, carboxyl, C₁-C₇ alkoxy, C₁-C₇ alkyl,C₁-C₇ haloalkyl, C₁-C₇ haloalkyloxy, C₁-C₇ hydroxyalkyl, C₁-C₇ alkenyl,C₁-C₇ alkyl-C(═O)O—, C₁-C₇ alkyl-C(═O)—, C₁-C₇ alkynyl, halo,hydroxyalkoxy, C₁-C₇ alkyl-NHSO₂—, C₁-C₇ alkyl-SO₂NH—, C₁-C₇alkylsulfonyl, C₁-C₇ alkylamino or di(C₁-C₇)alkylamino.

In one embodiment, R³ is H.

In one embodiment, R⁴ is selected from —NR⁶R⁷,

In another embodiment, R⁴ is —NR⁶R⁷.

In one embodiment, R⁵ is H. In another embodiment, R⁵ is independentlyselected from H, OH, NH₂, nitro, CN, amide, carboxyl, C₁-C₂ alkoxy,C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ haloalkyloxy, C₁-C₂ hydroxyalkyl,C₁-C₂ alkenyl, C₁-C₂alkyl-C(═O)O—, C₁-C₂ alkyl-C(═O)—, C₁-C₂ alkynyl,halo, hydroxyalkoxy, C₁-C₂ alkyl-NHSO₂—, C₁-C₂ alkyl-SO₂NH—, C₁-C₂alkylsulfonyl, C₁-C₂ alkylamino or di(C₁-C₂)alkylamino.

In one embodiment, R⁶ is selected from H or C₁-C₄ alkyl.

In one embodiment, R⁷ is selected from H, —(CR^(a) ₂)_(q)O(CR^(a)₂)_(q)R¹², —C(O)(CR^(a) ₂)_(q)R¹³, —(CR^(a) ₂)_(v)C(O)NR¹¹ or —(CR^(a)₂)_(v)NR¹¹. In one embodiment, R⁷ is selected from H, —(CR^(a)₂)_(v)O(CR^(a) ₂)_(q)R¹², —C(O)(CR^(a) ₂)_(q)R¹³ or —(CR^(a) ₂)_(v)NR¹¹.In another embodiment, R⁷ is selected from —C(O)(CR^(a) ₂)_(q)R¹³ or—(CR^(a) ₂)_(v)NR¹¹. In another embodiment, R⁷ is —C(O)(CR^(a)₂)_(q)R¹³. In one embodiment, R⁷ is —C(O)O(CR^(a) ₂)_(q)R¹².

In one embodiment, R⁸ is independently selected from H, C₁-C₄ alkyl,N(R⁶)₂, —(CR^(a) ₂)_(q)R¹² or when m is at least 2, two adjacent R⁸ forman aryl ring.

In one embodiment, R⁹ is H or C₁-C₄ alkyl.

In one embodiment, R¹⁰ is selected from H, C₃-C₆ cycloalkyl, pyridyl,thienyl, pyrazolyl or thiazolyl; wherein cycloalkyl, pyridyl, thienyl,pyrazolyl or thiazolyl is optionally substituted with aryl, heteroaryl,halo, C₁-C₄ alkyl, N(R⁶)₂, OH, C₁-C₄ alkoxy or C₁-C₄ haloalkyl.

In one embodiment, R¹⁰ is selected from H, C₃-C₆ cycloalkyl, pyridyl,thienyl, pyrazolyl or thiazolyl; wherein cycloalkyl, pyridyl, thienyl,pyrazolyl or thiazolyl is optionally substituted with OH, NH₂, nitro,CN, amide, carboxyl, C₁-C₇ alkoxy, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇haloalkyloxy, C₁-C₇ hydroxyalkyl, C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—,C₁-C₇ alkyl-C(═O)—, C₁-C₇ alkynyl, halo, hydroxyalkoxy, C₁-C₇alkyl-NHSO₂—, C₁-C₇ alkyl-SO₂NH—, C₁-C₇ alkylsulfonyl, C₁-C₇ alkylamino,di(C₁-C₇)alkylamino, aryl, heterocyclic or cycloalkyl.

In a further embodiment, R¹⁰ is pyridyl. In a particular embodiment, R¹⁰is pyridin-3-yl. In a particular embodiment, R¹⁰ is pyridin-4-yl. In aparticular embodiment, R¹⁰ is pyridin-2-yl. In one embodiment, R¹⁰ ismethyl. In another embodiment, R¹⁰ is ethyl. In a further embodiment,R¹⁰ is propyl.

In one embodiment, R¹¹ is independently selected from H, C₁-C₄ alkyl,C₃-C₆ cycloalkyl, heteroaryl, aryl or heterocyclic, C₃-C₆alkylcycloalkyl, alkylheteroaryl, alkylaryl or alkylheterocyclic,wherein the alkyl, cycloalkyl, heteroaryl, heterocyclic, aryl,alkylcycloalkyl, alkylheteroaryl, alkylheterocyclic, or alkylaryl isoptionally substituted with aryl, heteroaryl, halo, C₁-C₄ alkyl, N(R⁶)₂,OH, C₁-C₄ alkoxy or C₁-C₄ haloalkyl.

In one embodiment, R¹¹ is independently selected from H, C₁-C₄ alkyl,C₃-C₆ cycloalkyl, heteroaryl, aryl or heterocyclic, C₃-C₆alkylcycloalkyl, alkylheteroaryl, alkylaryl or alkylheterocyclic,wherein the alkyl, cycloalkyl, heteroaryl, heterocyclic, aryl,alkylcycloalkyl, alkylheteroaryl, alkylheterocyclic, or alkylaryl isoptionally substituted with OH, NH₂, nitro, CN, amide, carboxyl, C₁-C₇alkoxy, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇ haloalkyloxy, C₁-C₇hydroxyalkyl, C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—, C₁-C₇ alkyl-C(═O)—,C₁-C₇ alkynyl, halo, hydroxyalkoxy, C₁-C₇ alkyl-NHSO₂—, C₁-C₇alkyl-SO₂NH—, C₁-C₇ alkylsulfonyl, C₁-C₇ alkylamino,di(C₁-C₇)alkylamino, aryl, heterocyclic or cycloalkyl.

In another embodiment, R¹¹ is selected from H, C₁-C₄ alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, alkylheteroaryl or heteroaryl. Inanother embodiment, R¹¹ is selected from C₁-C₄ alkyl or alkylheteroaryl.In a further embodiment, R¹¹ is alkylheteroaryl. In a particularembodiment, R¹¹ is —CH₂-pyridyl. In a particular embodiment, R¹¹ is—CH₂-pyridin-3-yl. In a particular embodiment, R¹¹ is —CH₂-pyridin-4-yl.In a particular embodiment, R¹¹ is —CH₂-pyridin-2-yl. In one embodiment,R¹¹ is methyl. In another embodiment, R¹¹ is ethyl. In a furtherembodiment, R¹¹ is propyl.

In one embodiment, R¹² is selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, heteroaryl, aryl or heterocyclic, wherein the alkyl,cycloalkyl, heteroaryl, heterocyclic or aryl is optionally substitutedwith aryl, heteroaryl, halo, C₁-C₄ alkyl, N(R⁶)₂, OH, C₁-C₄ alkoxy orC₁-C₄ haloalkyl.

In one embodiment, R¹² is selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, heteroaryl, aryl or heterocyclic, wherein the alkyl,cycloalkyl, heteroaryl, heterocyclic or aryl is optionally substitutedwith OH, NH₂, nitro, CN, amide, carboxyl, C₁-C₇ alkoxy, C₁-C₇ alkyl,C₁-C₇ haloalkyl, C₁-C₇ haloalkyloxy, C₁-C₇ hydroxyalkyl, C₁-C₇ alkenyl,C₁-C₇alkyl-C(═O)O—, C₁-C₇ alkyl-C(═O)—, C₁-C₇ alkynyl, halo,hydroxyalkoxy, C₁-C₇ alkyl-NHSO₂—, C₁-C₇ alkyl-SO₂NH—, C₁-C₇alkylsulfonyl, C₁-C₇ alkylamino, di(C₁-C₇)alkylamino, aryl, heterocyclicor cycloalkyl.

In another embodiment, R¹² is selected from H, C₁-C₄ alkyl, cycloalkyl,aryl, or heteroaryl. In another embodiment, R¹² is selected from C₁-C₄alkyl or heteroaryl. In a further embodiment, R¹² is heteroaryl. In aparticular embodiment, R¹² is pyridyl. In a particular embodiment, R¹²is pyridin-3-yl. In a particular embodiment, R¹² is pyridin-4-yl. In aparticular embodiment, R¹² is pyridin-2-yl. In one embodiment, R¹² ismethyl. In another embodiment, R¹² is ethyl. In a further embodiment,R¹² is propyl.

In one embodiment, R¹³ is selected from H, C₂-C₇ alkyl, C₃-C₈cycloalkyl, heteroaryl, or aryl, wherein the cycloalkyl, heteroaryl oraryl is optionally substituted with aryl, heteroaryl, halo, C₁-C₄ alkyl,N(R⁶)₂, OH, C₁-C₄ alkoxy or C₁-C₄ haloalkyl.

In one embodiment, R¹³ is selected from H, C₂-C₇ alkyl, C₃-C₈cycloalkyl, heteroaryl, or aryl, wherein the cycloalkyl, heteroaryl oraryl is optionally substituted with OH, NH₂, nitro, CN, amide, carboxyl,C₁-C₇ alkoxy, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇ haloalkyloxy, C₁-C₇hydroxyalkyl, C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—, C₁-C₇ alkyl-C(═O)—,C₁-C₇ alkynyl, halo, hydroxyalkoxy, C₁-C₇alkyl-NHSO₂—, C₁-C₇alkyl-SO₂NH—, C₁-C₇ alkylsulfonyl, C₁-C₇ alkylamino,di(C₁-C₇)alkylamino, aryl, heterocyclic or cycloalkyl.

In another embodiment, R¹³ is selected from H, C₁-C₄ alkyl, cycloalkyl,aryl, or heteroaryl. In another embodiment, R¹³ is selected from C₁-C₄alkyl or heteroaryl. In a further embodiment, R¹³ is heteroaryl. In aparticular embodiment, R¹³ is pyridyl. In a particular embodiment, R¹³is pyridin-3-yl. In a particular embodiment, R¹³ is pyridin-4-yl. In aparticular embodiment, R¹³ is pyridin-2-yl. In one embodiment, R¹³ ismethyl. In another embodiment, R¹³ is ethyl. In a further embodiment,R¹³ is propyl.

In one embodiment, R^(a) is H.

In one embodiment, Ring B is heteroaryl or aryl. In a furtherembodiment, Ring B is phenyl. In another embodiment, Ring B is

In one embodiment, m is 1, 2, 3, 4, 5, 6, 7, or 8. In anotherembodiment, m is 1 or 2.

In one embodiment, p is 1, 2, 3 or 4. In another embodiment, p is 1.

In one embodiment, q is independently 0, 1, 2, 3, or 4. In anotherembodiment, q is independently 0, 1 or 2. In a further embodiment, q is0. In a further embodiment, q is 1. In a further embodiment, q is 2.

In one embodiment, t is 1 or 2. In one embodiment, v is 1 or 2.

In one embodiment, L¹ is ethenyl or a bond. In another embodiment, L¹ isa bond.

In one embodiment, X is OH or NH₂. In another embodiment, X is NH₂.

Stereochemistry

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and l or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the Formulas of the invention, it isunderstood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the Formula. As is used in the art, when it is desired to specifythe absolute configuration about a chiral carbon, one of the bonds tothe chiral carbon can be depicted as a wedge (bonds to atoms above theplane) and the other can be depicted as a series or wedge of shortparallel lines is (bonds to atoms below the plane). TheCahn-Inglod-Prelog system can be used to assign the (R) or (S)configuration to a chiral carbon.

When the HDAC inhibitors of the present invention contain one chiralcenter, the compounds exist in two enantiomeric forms and the presentinvention includes both enantiomers and mixtures of enantiomers, such asthe specific 50:50 mixture referred to as a racemic mixtures. Theenantiomers can be resolved by methods known to those skilled in theart, such as formation of diastereoisomeric salts which may beseparated, for example, by crystallization (see, CRC Handbook of OpticalResolutions via Diastereomeric Salt Formation by David Kozma (CRC Press,2001)); formation of diastereoisomeric derivatives or complexes whichmay be separated, for example, by crystallization, gas-liquid or liquidchromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by one ofthe separation procedures described above, a further step is required toliberate the desired enantiomeric form. Alternatively, specificenantiomers may be synthesized by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon ofthe compounds of the invention is understood to mean that the designatedenantiomeric form of the compounds is in enantiomeric excess (ee) or inother words is substantially free from the other enantiomer. Forexample, the “R” forms of the compounds are substantially free from the“S” forms of the compounds and are, thus, in enantiomeric excess of the“S” forms. Conversely, “S” forms of the compounds are substantially freeof “R” forms of the compounds and are, thus, in enantiomeric excess ofthe “R” forms. Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%. In a particular embodimentwhen a specific absolute configuration is designated, the enantiomericexcess of depicted compounds is at least about 90%.

When a compound of the present invention has two or more chiral carbonsit can have more than two optical isomers and can exist indiastereoisomeric forms. For example, when there are two chiral carbons,the compound can have up to 4 optical isomers and 2 pairs of enantiomers((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g.,(S,S)/(R,R)) are mirror image stereoisomers of one another. Thestereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) arediastereomers. The diastereoisomeric pairs may be separated by methodsknown to those skilled in the art, for example chromatography orcrystallization and the individual enantiomers within each pair may beseparated as described above. The present invention includes eachdiastereoisomer of such compounds and mixtures thereof.

As used herein, “a,” an” and “the” include singular and plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an active agent” or “a pharmacologically active agent”includes a single active agent as well a two or more different activeagents in combination, reference to “a carrier” includes mixtures of twoor more carriers as well as a single carrier, and the like.

This invention is also intended to encompass pro-drugs of the4-carboxybenzylamino derivatives disclosed herein. A prodrug of any ofthe compounds can be made using well-known pharmacological techniques.

This invention, in addition to the above listed compounds, is intendedto encompass the use of homologs and analogs of such compounds. In thiscontext, homologs are molecules having substantial structuralsimilarities to the above-described compounds and analogs are moleculeshaving substantial biological similarities regardless of structuralsimilarities.

Pharmaceutically Acceptable Salts

The 4-carboxybenzylamino derivatives described herein can, as notedabove, be prepared in the form of their pharmaceutically acceptablesalts. Pharmaceutically acceptable salts are salts that retain thedesired biological activity of the parent compound and do not impartundesired toxicological effects. Examples of such salts are (a) acidaddition salts organic and inorganic acids, for example, acid additionsalts which may, for example, be hydrochloric acid, sulphuric acid,methanesulphonic acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonicacid, phosphoric acid, trifluoroacetic acid, formic acid and the like.Pharmaceutically acceptable salts can also be prepared from by treatmentwith inorganic bases, for example, sodium, potassium, ammonium, calcium,or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.Pharmaceutically acceptable salts can also be formed from elementalanions such as chlorine, bromine and iodine.

The active compounds disclosed can, as noted above, also be prepared inthe form of their hydrates. The term “hydrate” includes but is notlimited to hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrateand the like.

The active compounds disclosed can, as noted above, also be prepared inthe form of a solvate with any organic or inorganic solvent, for examplealcohols such as methanol, ethanol, propanol and isopropanol, ketonessuch as acetone, aromatic solvents and the like.

The active compounds disclosed can also be prepared in any solid orliquid physical form. For example, the compound can be in a crystallineform, in amorphous form, and have any particle size. Furthermore, thecompound particles may be micronized, or may be agglomerated,particulate granules, powders, oils, oily suspensions or any other formof solid or liquid physical form.

The compounds of the present invention may also exhibit polymorphism.This invention further includes different polymorphs of the compounds ofthe present invention. The term “polymorph” refers to a particularcrystalline state of a substance, having particular physical propertiessuch as X-ray diffraction, IR spectra, melting point, and the like.

As used herein, “a,” an” and “the” include singular and plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an active agent” or “a pharmacologically active agent”includes a single active agent as well a two or more different activeagents in combination, reference to “a carrier” includes mixtures of twoor more carriers as well as a single carrier, and the like.

Methods of Treatment

The invention also relates to methods of using the 4-carboxybenzylaminoderivatives described herein. As demonstrated herein, the4-carboxybenzylamino derivatives of the present invention are useful forthe treatment of cancer. In addition, there is a wide range of otherdiseases for which 4-carboxybenzylamino derivatives may be found useful.Non-limiting examples are thioredoxin (TRX)-mediated diseases asdescribed herein, and diseases of the central nervous system (CNS) asdescribed herein.

1. Treatment of Cancer

As demonstrated herein, the 4-carboxybenzylamino derivatives of thepresent invention are useful for the treatment of cancer. Accordingly,in one embodiment, the invention relates to a method of treating cancerin a subject in need of treatment comprising administering to saidsubject a therapeutically effective amount of the 4-carboxybenzylaminoderivatives described herein.

The term “cancer” refers to any cancer caused by the proliferation ofneoplastic cells, such as solid tumors, neoplasms, carcinomas, sarcomas,leukemias, lymphomas and the like. In particular, cancers that may betreated by the compounds, compositions and methods of the inventioninclude, but are not limited to: Cardiac: sarcoma (angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma,fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamouscell, undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma; and Adrenal glands: neuroblastoma. Thus, the term“cancerous cell” as provided herein, includes a cell afflicted by anyone of the above-identified conditions.

In an embodiment, the instant compounds are useful in the treatment ofcancers that include, but are not limited to: leukemias including acuteleukemias and chronic leukemias such as acute lymphocytic leukemia(ALL), Acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML) and Hairy Cell Leukemia; lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), Hodgkin'sdisease and non-Hodgkin's lymphomas, large-cell lymphomas, diffuse largeB-cell lymphoma (DLBCL); Burkitt's lymphoma; mesothelioma, primarycentral nervous system (CNS) lymphoma; multiple myeloma; childhood solidtumors such as brain tumors, neuroblastoma, retinoblastoma, Wilm'stumor, bone tumors, and soft-tissue sarcomas, common solid tumors ofadults such as head and neck cancers (e.g., oral, laryngeal andesophageal), genito urinary cancers (e.g., prostate, bladder, renal,uterine, ovarian, testicular, rectal and colon), lung cancer, breastcancer, pancreatic cancer, melanoma and other skin cancers, stomachcancer, brain tumors, liver cancer and thyroid cancer.

2. Treatment of Thioredoxin (TRX)-Mediated Diseases

In another embodiment, the 4-carboxybenzylamino derivatives are used ina method of treating a thioredoxin (TRX)-mediated disease or disorder ina subject in need thereof, comprising administering to the subject atherapeutically effective amount of one or more of the4-carboxybenzylamino compounds described herein.

Examples of TRX-mediated diseases include, but are not limited to, acuteand chronic inflammatory diseases, autoimmune diseases, allergicdiseases, diseases associated with oxidative stress, and diseasescharacterized by cellular hyperproliferation.

Non-limiting examples are inflammatory conditions of a joint includingrheumatoid arthritis (RA) and psoriatic arthritis; inflammatory boweldiseases such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fascitis; cancers with leukocyteinfiltration of the skin or organs, ischemic injury, including cerebralischemia (e.g., brain injury as a result of trauma, epilepsy, hemorrhageor stroke, each of which may lead to neurodegeneration); HIV, heartfailure, chronic, acute or malignant liver disease, autoimmunethyroiditis; systemic lupus erythematosus, Sjorgren's syndrome, lungdiseases (e.g., ARDS); acute pancreatitis; amyotrophic lateral sclerosis(ALS); Alzheimer's disease; cachexia/anorexia; asthma; atherosclerosis;chronic fatigue syndrome, fever; diabetes (e.g., insulin diabetes orjuvenile onset diabetes); glomerulonephritis; graft versus hostrejection (e.g., in transplantation); hemohorragic shock; hyperalgesia:inflammatory bowel disease; multiple sclerosis; myopathies (e.g., muscleprotein metabolism, esp. in sepsis); osteoporosis; Parkinson's disease;pain; pre-term labor; psoriasis; reperfusion injury; cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock); side effects fromradiation therapy, temporal mandibular joint disease, tumor metastasis;or an inflammatory condition resulting from strain, sprain, cartilagedamage, trauma such as burn, orthopedic surgery, infection or otherdisease processes. Allergic diseases and conditions, include but are notlimited to respiratory allergic diseases such as asthma, allergicrhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilicpneumonia), delayed-type hypersensitivity, interstitial lung diseases(ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated withrheumatoid arthritis, systemic lupus erythematosus, ankylosingspondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis ordermatomyositis); systemic anaphylaxis or hypersensitivity responses,drug allergies (e.g., to penicillin, cephalosporins), insect stingallergies, and the like.

3. Treatment of Diseases of the Central Nervous System (CNS)

In another embodiment, the 4-carboxybenzylamino derivatives are used ina method of treating a disease of the central nervous system in asubject in need thereof comprising administering to the subject atherapeutically effective amount of any one or more of the4-carboxybenzylamino compounds described herein.

In a particular embodiment, the CNS disease is a neurodegenerativedisease. In a further embodiment, the neurodegenerative disease is aninherited neurodegenerative disease, such as those inheritedneurodegenerative diseases that are polyglutamine expansion diseases.Generally, neurodegenerative diseases can be grouped as follows:

I. Disorders characterized by progressive dementia in the absence ofother prominent neurologic signs, such as Alzheimer's disease; Seniledementia of the Alzheimer type; and Pick's disease (lobar atrophy).II. Syndromes combining progressive dementia with other prominentneurologic abnormalities such as A) syndromes appearing mainly in adults(e.g., Huntington's disease, Multiple system atrophy combining dementiawith ataxia and/or manifestations of Parkinson's disease, Progressivesupranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy bodydisease, and corticodentatonigral degeneration); and B) syndromesappearing mainly in children or young adults (e.g., Hallervorden-Spatzdisease and progressive familial myoclonic epilepsy).III. Syndromes of gradually developing abnormalities of posture andmovement such as paralysis agitans (Parkinson's disease), striatonigraldegeneration, progressive supranuclear palsy, torsion dystonia (torsionspasm; dystonia musculorum deformans), spasmodic torticollis and otherdyskinesis, familial tremor, and Gilles de la Tourette syndrome.IV. Syndromes of progressive ataxia such as cerebellar degenerations(e.g., cerebellar cortical degeneration and olivopontocerebellar atrophy(OPCA)); and spinocerebellar degeneration (Friedreich's atazia andrelated disorders).V. Syndrome of central autonomic nervous system failure (Shy-Dragersyndrome).VI. Syndromes of muscular weakness and wasting without sensory changes(motorneuron disease such as amyotrophic lateral sclerosis, spinalmuscular atrophy (e.g., infantile spinal muscular atrophy(Werdnig-Hoffman), juvenile spinal muscular atrophy(Wohlfart-Kugelberg-Welander) and other forms of familial spinalmuscular atrophy), primary lateral sclerosis, and hereditary spasticparaplegia.VII. Syndromes combining muscular weakness and wasting with sensorychanges (progressive neural muscular atrophy; chronic familialpolyneuropathies) such as peroneal muscular atrophy(Charcot-Marie-Tooth), hypertrophic interstitial polyneuropathy(Dejerine-Sottas), and miscellaneous forms of chronic progressiveneuropathy.VIII. Syndromes of progressive visual loss such as pigmentarydegeneration of the retina (retinitis pigmentosa), and hereditary opticatrophy (Leber's disease).

DEFINITIONS

The term “treating” in its various grammatical forms in relation to thepresent invention refers to preventing (i.e., chemoprevention), curing,reversing, attenuating, alleviating, minimizing, suppressing or haltingthe deleterious effects of a disease state, disease progression, diseasecausative agent (e.g., bacteria or viruses) or other abnormal condition.For example, treatment may involve alleviating a symptom (i.e., notnecessary all symptoms) of a disease or attenuating the progression of adisease. Because some of the inventive methods involve the physicalremoval of the etiological agent, the artisan will recognize that theyare equally effective in situations where the inventive compound isadministered prior to, or simultaneous with, exposure to the etiologicalagent (prophylactic treatment) and situations where the inventivecompounds are administered after (even well after) exposure to theetiological agent.

Treatment of cancer, as used herein, refers to partially or totallyinhibiting, delaying or preventing the progression of cancer includingcancer metastasis; inhibiting, delaying or preventing the recurrence ofcancer including cancer metastasis; or preventing the onset ordevelopment of cancer (chemoprevention) in a mammal, for example ahuman.

As used herein, the term “therapeutically effective amount” means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician. The therapeutic effect is dependent upon the disease ordisorder being treated or the biological effect desired. As such, thetherapeutic effect can be a decrease in the severity of symptomsassociated with the disease or disorder and/or inhibition (partial orcomplete) of progression of the disease. The amount needed to elicit thetherapeutic response can be determined based on the age, health, sizeand sex of the subject. Optimal amounts can also be determined based onmonitoring of the subject's response to treatment.

In the present invention, when the compounds are used to treat orprevent cancer, the desired biological response is partial or totalinhibition, delay or prevention of the progression of cancer includingcancer metastasis; inhibition, delay or prevention of the recurrence ofcancer including cancer metastasis; or the prevention of the onset ordevelopment of cancer (chemoprevention) in a mammal, for example ahuman.

Furthermore, in the present invention, when the compounds are used totreat and/or prevent thioredoxin (TRX)-mediated diseases and conditions,a therapeutically effective amount is an amount that regulates, forexample, increases, decreases or maintains a physiologically suitablelevel of TRX in the subject in need of treatment to elicit the desiredtherapeutic effect. The therapeutic effect is dependent upon thespecific TRX-mediated disease or condition being treated. As such, thetherapeutic effect can be a decrease in the severity of symptomsassociated with the disease or disorder and/or inhibition (partial orcomplete) of progression of the disease or disease.

Furthermore, in the present invention, when the compounds are used totreat and/or prevent diseases or disorders of the central nervous system(CNS), a therapeutically effective amount is dependent upon the specificdisease or disorder being treated. As such, the therapeutic effect canbe a decrease in the severity of symptoms associated with the disease ordisorder and/or inhibition (partial or complete) of progression of thedisease or disorder.

In addition, a therapeutically effective amount can be an amount thatinhibits histone deacetylase.

Further, a therapeutically effective amount, can be an amount thatselectively induces terminal differentiation, cell growth arrest and/orapoptosis of neoplastic cells, or an amount that induces terminaldifferentiation of tumor cells.

The method of the present invention is intended for the treatment orchemoprevention of human patients with cancer. However, it is alsolikely that the method would be effective in the treatment of cancer inother subjects. “Subject”, as used herein, refers to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, miceor other bovine, ovine, equine, canine, feline, rodent or murinespecies.

Histone Deacetylases and Histone Deacetylase Inhibitors

As demonstrated herein, the 4-carboxybenzylamino derivatives of thepresent invention show improved activity as histone deacetylase (HDAC)inhibitors. Accordingly, in one embodiment, the invention relates to amethod of inhibiting the activity of histone deacetylase comprisingcontacting the histone deacetylase with an effective amount of one ormore of the 4-carboxybenzylamino compounds described herein.

Histone deacetylases (HDACs), as that term is used herein, are enzymesthat catalyze the removal of acetyl groups from lysine residues in theamino terminal tails of the nucleosomal core histones. As such, HDACstogether with histone acetyl transferases (HATs) regulate theacetylation status of histones. Histone acetylation affects geneexpression and inhibitors of HDACs, such as the hydroxamic acid-basedhybrid polar compound suberoylanilide hydroxamic acid (SAHA) inducegrowth arrest, differentiation and/or apoptosis of transformed cells invitro and inhibit tumor growth in vivo. HDACs can be divided into threeclasses based on structural homology. Class I HDACs (HDACs 1, 2, 3 and8) bear similarity to the yeast RPD3 protein, are located in the nucleusand are found in complexes associated with transcriptionalco-repressors. Class II HDACs (HDACs 4, 5, 6, 7 and 9) are similar tothe yeast HDA1 protein, and have both nuclear and cytoplasmicsubcellular localization. Both Class I and II HDACs are inhibited byhydroxamic acid-based HDAC inhibitors, such as SAHA. Class III HDACsform a structurally distant class of NAD dependent enzymes that arerelated to the yeast SIR2 proteins and are not inhibited by hydroxamicacid-based HDAC inhibitors.

Histone deacetylase inhibitors or HDAC inhibitors, as that term is usedherein are compounds that are capable of inhibiting the deacetylation ofhistones in vivo, in vitro or both. As such, HDAC inhibitors inhibit theactivity of at least one histone deacetylase. As a result of inhibitingthe deacetylation of at least one histone, an increase in acetylatedhistone occurs and accumulation of acetylated histone is a suitablebiological marker for assessing the activity of HDAC inhibitors.Therefore, procedures that can assay for the accumulation of acetylatedhistones can be used to determine the HDAC inhibitory activity ofcompounds of interest. It is understood that compounds that can inhibithistone deacetylase activity can also bind to other substrates and assuch can inhibit other biologically active molecules such as enzymes. Itis also to be understood that the compounds of the present invention arecapable of inhibiting any of the histone deacetylases set forth above,or any other histone deacetylases.

For example, in patients receiving HDAC inhibitors, the accumulation ofacetylated histones in peripheral mononuclear cells as well as in tissuetreated with HDAC inhibitors can be determined against a suitablecontrol.

HDAC inhibitory activity of a particular compound can be determined invitro using, for example, an enzymatic assays which shows inhibition ofat least one histone deacetylase. Further, determination of theaccumulation of acetylated histones in cells treated with a particularcomposition can be determinative of the HDAC inhibitory activity of acompound.

Assays for the accumulation of acetylated histones are well known in theliterature. See, for example, Marks, P. A. et al., J. Natl. CancerInst., 92:1210-1215, 2000, Butler, L. M. et al., Cancer Res.60:5165-5170 (2000), Richon, V. M. et al., Proc. Natl. Acad. Sci., USA,95:3003-3007, 1998, and Yoshida, M. et al., J. Biol. Chem.,265:17174-17179, 1990.

For example, an enzymatic assay to determine the activity of an HDACinhibitor compound can be conducted as follows. Briefly, the effect ofan HDAC inhibitor compound on affinity purified human epitope-tagged(Flag) HDAC1 can be assayed by incubating the enzyme preparation in theabsence of substrate on ice for about 20 minutes with the indicatedamount of inhibitor compound. Substrate ([³H]acetyl-labelled murineerythroleukemia cell-derived histone) can be added and the sample can beincubated for 20 minutes at 37° C. in a total volume of 30 μL. Thereaction can then be stopped and released acetate can be extracted andthe amount of radioactivity release determined by scintillationcounting. An alternative assay useful for determining the activity of anHDAC inhibitor compound is the “HDAC Fluorescent Activity Assay; DrugDiscovery Kit-AK-500” available from BIOMOL Research Laboratories, Inc.,Plymouth Meeting, Pa.

In vivo studies can be conducted as follows. Animals, for example, mice,can be injected intraperitoneally with an HDAC inhibitor compound.Selected tissues, for example, brain, spleen, liver etc, can be isolatedat predetermined times, post administration. Histones can be isolatedfrom tissues essentially as described by Yoshida et al., J. Biol. Chem.265:17174-17179, 1990. Equal amounts of histones (about 1 μg) can beelectrophoresed on 15% SDS-polyacrylamide gels and can be transferred toHybond-P filters (available from Amersham). Filters can be blocked with3% milk and can be probed with a rabbit purified polyclonalanti-acetylated histone H4 antibody (αAc-H4) and anti-acetylated histoneH3 antibody (αAc-H3) (Upstate Biotechnology, Inc.). Levels of acetylatedhistone can be visualized using a horseradish peroxidase-conjugated goatanti-rabbit antibody (1:5000) and the SuperSignal chemiluminescentsubstrate (Pierce). As a loading control for the histone protein,parallel gels can be run and stained with Coomassie Blue (CB).

In addition, hydroxamic acid-based HDAC inhibitors have been shown to upregulate the expression of the p21^(WAF1) gene. The p21^(WAF1) proteinis induced within 2 hours of culture with HDAC inhibitors in a varietyof transformed cells using standard methods. The induction of thep21^(WAF1) gene is associated with accumulation of acetylated histonesin the chromatin region of this gene. Induction of p21^(WAF1) cantherefore be recognized as involved in the G1 cell cycle arrest causedby HDAC inhibitors in transformed cells.

Combination Therapy

The 4-carboxybenzylamino compounds of the present invention can beadministered alone or in combination with other therapies suitable forthe disease or disorder being treated. Where separate dosageformulations are used, the 4-carboxybenzylamino compound and the othertherapeutic agent can be administered at essentially the same time(concurrently) or at separately staggered times (sequentially). Thepharmaceutical combination is understood to include all these regimens.Administration in these various ways are suitable for the presentinvention as long as the beneficial therapeutic effect of the4-carboxybenzylamino compound and the other therapeutic agent arerealized by the patient at substantially the same time. In anembodiment, such beneficial effect is achieved when the target bloodlevel concentrations of each active drug are maintained at substantiallythe same time.

The instant compounds are also useful in combination with knowntherapeutic agents and anti-cancer agents. For example, instantcompounds are useful in combination with known anti-cancer agents.Combinations of the presently disclosed compounds with other anti-canceror chemotherapeutic agents are within the scope of the invention.Examples of such agents can be found in Cancer Principles and Practiceof Oncology by V. T. Devita and S. Hellman (editors), 6^(th) edition(Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person ofordinary skill in the art would be able to discern which combinations ofagents would be useful based on the particular characteristics of thedrugs and the cancer involved. Such anti-cancer agents include, but arenot limited to, the following: estrogen receptor modulators, androgenreceptor modulators, retinoid receptor modulators, cytotoxic/cytostaticagents, antiproliferative agents, prenyl-protein transferase inhibitors,HMG-CoA reductase inhibitors and other angiogenesis inhibitors,inhibitors of cell proliferation and survival signaling, apoptosisinducing agents, agents that interfere with cell cycle checkpoints,agents that interfere with receptor tyrosine kinases (RTKs) and cancervaccines. The instant compounds are particularly useful whenco-administered with radiation therapy.

In an embodiment, the instant compounds are also useful in combinationwith known anti-cancer agents including the following: estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic agents, antiproliferative agents, prenyl-protein transferaseinhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors, and other angiogenesis inhibitors.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, diethylstilbestrol, tamoxifen, raloxifene, idoxifene,LY353381, LY117081, toremifene, fluoxymestero, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

Other hormonal agents include: aromatase inhibitors (e.g.,aminoglutethimide, anastrozole and tetrazole), luteinizing hormonerelease hormone (LHRH) analogues, ketoconazole, goserelin acetate,leuprolide, megestrol acetate and mifepristone.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of histonedeacetylase, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, topoisomerase inhibitors, proteasomeinhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine,melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine,streptozocin, tasonermin, lonidamine, carboplatin, altretamine,dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosilate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, porfiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin,mitomycin C, dactinomycin, plicatomycin, bisantrene, mitoxantrone,pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, ansamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include but are not limited tolactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude vincristine, vinblastine, vindesine, vinzolidine, vinorelbine,vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine,podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)),paclitaxel, docetaxol, rhizoxin, dolastatin, mivobulin isethionate,auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycamptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine, (5a, 5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydro0xy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in PCT Publications WO 01/30768, WO01/98278, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO03/049,678 and WO 03/39460 and pending PCT Appl. Nos. US03/06403 (filedMar. 4, 2003), US03/15861 (filed May 19, 2003), US03/15810 (filed May19, 2003), US03/18482 (filed Jun. 12, 2003) and US03/18694 (filed Jun.12, 2003). In an embodiment inhibitors of mitotic kinesins include, butare not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors ofCENP-E, inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosph1and inhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, SAHA, TSA, oxamflatin, PXD101, MG98, valproic acid andscriptaid. Further reference to other histone deacetylase inhibitors maybe found in the following manuscript; Miller, T. A. et al. J. Med. Chem.46(24):5097-5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, floxuridine, methotrexate,leucovorin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP),cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA),asparaginase, gemcitabine, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1′-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®, see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structuralformulas of these and additional HMG-CoA reductase inhibitors that maybe used in the instant methods are described at page 87 of M. Yalpani,“Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb.1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoAreductase inhibitor as used herein includes all pharmaceuticallyacceptable lactone and open-acid forms (i.e., where the lactone ring isopened to form the free acid) as well as salt and ester forms ofcompounds which have HMG-CoA reductase inhibitory activity, and thereforthe use of such salts, esters, open-acid and lactone forms is includedwithin the scope of this invention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12,erythropoietin (epoietin-α), granulocyte-CSF (filgrastin), granulocyte,macrophage-CSF (sargramostim), pentosan polysulfate, cyclooxygenaseinhibitors, including nonsteroidal anti-inflammatories (NSAIDs) likeaspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitorslike celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol.69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p. 573 (1990); Anat.Rec., Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995);Clin, Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol. 16, p.107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res.,Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol.Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)),steroidal anti-inflammatories (such as corticosteroids,mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred,betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab.Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, NatureBiotechnology, Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature,362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in PCT Publication WO03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that interfere with receptor tyrosine kinases (RTKs)” refer tocompounds that inhibit RTKs and therefore mechanisms involved inoncogenesis and tumor progression. Such agents include inhibitors ofc-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors ofRTKs shown as described by Bume-Jensen and Hunter, Nature, 411:355-365,2001.

“Inhibitors of cell proliferation and survival signaling pathway” referto pharmaceutical agents that inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of inhibitors of EGFR (for example gefitinib anderlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors ofIGFR, inhibitors of CD20 (rituximab), inhibitors of cytokine receptors,inhibitors of MET, inhibitors of PI3K (for example LY294002),serine/threonine kinases (including but not limited to inhibitors of Aktsuch as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02/083138),inhibitors of Raf kinase (for example BAY-43-9006), inhibitors of MEK(for example CI-1040 and PD-098059) and inhibitors of mTOR (for exampleWyeth CCI-779 and Ariad AP23573). Such agents include small moleculeinhibitor compounds and antibody antagonists.

“Apoptosis inducing agents” include activators of TNF receptor familymembers (including the TRAIL receptors).

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. No. 5,474,995, U.S. Pat. No.5,861,419, U.S. Pat. No. 6,001,843, U.S. Pat. No. 6,020,343, U.S. Pat.No. 5,409,944, U.S. Pat. No. 5,436,265, U.S. Pat. No. 5,536,752, U.S.Pat. No. 5,550,142, U.S. Pat. No. 5,604,260, U.S. Pat. No. 5,698,584,U.S. Pat. No. 5,710,140, WO 94/15932, U.S. Pat. No. 5,344,991, U.S. Pat.No. 5,134,142, U.S. Pat. No. 5,380,738, U.S. Pat. No. 5,393,790, U.S.Pat. No. 5,466,823, U.S. Pat. No. 5,633,272, and U.S. Pat. No.5,932,598.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;and5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; ora pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceuticallyacceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the αvβ5 integrin, tocompounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-643-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, imatinib (STI571), CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of theinstantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists andPPAR-6 (i.e., PPAR-delta) agonists are useful in the treatment ofcertain malignancies. PPAR-γ and PPAR-6 are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999; 274:9116-9121; Invest. Ophthalmol Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice. (Arch. Ophthamol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the treatmentof cancer. For an overview of genetic strategies to treating cancer seeHall et al (Am J Hum Genet 61:785-789, 1997) and Kufe et al (CancerMedicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapycan be used to deliver any tumor suppressing gene. Examples of suchgenes include, but are not limited to, p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example), Duc-4, NF-1, NF-2, RB, WT1, BRCA1, BRCA2, a uPA/uPARantagonist (“Adenovirus-Mediated Delivery of a uPA/uPAR AntagonistSuppresses Angiogenesis-Dependent Tumor Growth and Dissemination inMice,” Gene Therapy, August 1998; 5(8):1105-13), and interferon gamma(J. Immunol. 2000; 164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleproclorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In an embodiment, an anti-emesis agentselected from a neurokinin-1 receptor antagonist, a 5HT3 receptorantagonist and a corticosteroid is administered as an adjuvant for thetreatment or prevention of emesis that may result upon administration ofthe instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous erythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, bacillusCalmette-Guerin, octreotide, isoprinosine and Zadaxin.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be useful for treating orpreventing breast cancer in combination with aromatase inhibitors.Examples of aromatase inhibitors include but are not limited toanastrozole, letrozole and exemestane.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with compounds which induce terminaldifferentiation of the neoplastic cells. Suitable differentiation agentsinclude the compounds disclosed in any one or more of the followingreferences.

-   a) Polar compounds (Marks et al (1987); Friend, C., Scher, W.,    Holland, J. W., and Sato, T. (1971) Proc. Natl. Acad. Sci. (USA) 68:    378-382; Tanaka, M., Levy, J., Terada, M., Breslow, R., Rifkind, R.    A., and Marks, P. A. (1975) Proc. Natl. Acad. Sci. (USA) 72:    1003-1006; Reuben, R. C., Wife, R. L., Breslow, R., Rifkind, R. A.,    and Marks, P. A. (1976) Proc. Natl. Acad. Sci. (USA) 73: 862-866);-   b) Derivatives of vitamin D and retinoic acid (Abe, E., Miyaura, C.,    Sakagami, H., Takeda, M., Konno, K., Yamazaki, T., Yoshika, S., and    Suda, T. (1981) Proc. Natl. Acad. Sci. (USA) 78: 4990-4994;    Schwartz, E. L., Snoddy, J. R., Kreutter, D., Rasmussen, H., and    Sartorelli, A. C. (1983) Proc. Am. Assoc. Cancer Res. 24: 18;    Tanenaga, K., Hozumi, M., and Sakagami, Y. (1980) Cancer Res. 40:    914-919);-   c) Steroid hormones (Lotem, J. and Sachs, L. (1975) Int. J. Cancer    15: 731-740);-   d) Growth factors (Sachs, L. (1978) Nature (Lond.) 274: 535,    Metcalf, D. (1985) Science, 229: 16-22);-   e) Proteases (Scher, W., Scher, B. M., and Waxman, S. (1983) Exp.    Hematol. 11: 490-498; Scher, W., Scher, B. M., and Waxman, S. (1982)    Biochem. & Biophys. Res. Comm. 109: 348-354);-   f) Tumor promoters (Huberman, E. and Callaham, M. F. (1979) Proc.    Natl. Acad. Sci. (USA) 76: 1293-1297; Lottem, J. and    Sachs, L. (1979) Proc. Natl. Acad. Sci. (USA) 76: 5158-5162); and-   g) inhibitors of DNA or RNA synthesis (Schwartz, E. L. and    Sartorelli, A. C. (1982) Cancer Res. 42: 2651-2655, Terada, M.,    Epner, E., Nudel, U., Salmon, J., Fibach, E., Rifkind, R. A., and    Marks, P. A. (1978) Proc. Natl. Acad. Sci. (USA) 75: 2795-2799;    Morin, M. J. and Sartorelli, A. C. (1984) Cancer Res 44: 2807-2812;    Schwartz, E. L., Brown, B. J., Nierenberg, M., Marsh, J. C., and    Sartorelli, A. C. (1983) Cancer Res. 43: 2725-2730; Sugano, H.,    Furusawa, M., Kawaguchi, T., and Ikawa, Y. (1973) Bibl. Hematol. 39:    943-954; Ebert, P. S., Wars, I., and Buell, D. N. (1976) Cancer Res.    36: 1809-1813; Hayashi, M., Okabe, J., and Hozumi, M. (1979) Gann    70: 235-238).

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with γ-secretase inhibitors.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of Formula I in combination with radiation therapy and/or incombination with a second compound selected from: an estrogen receptormodulator, an androgen receptor modulator, a retinoid receptormodulator, a cytotoxiccytostatic agent, an antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anHIV protease inhibitor, a reverse transcriptase inhibitor, anangiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, an inhibitorof inherent multidrug resistance, an anti-emetic agent, an agent usefulin the treatment of anemia, an agent useful in the treatment ofneutropenia, an immunologic-enhancing drug, an inhibitor of cellproliferation and survival signaling, a bisphosphonate, an aromataseinhibitor, an siRNA therapeutic, γ-secretase inhibitors, agents thatinterfere with receptor tyrosine kinases (RTKs) and an agent thatinterferes with a cell cycle checkpoint.

The compounds of the instant invention are useful in combination withthe following therapeutic agents: abarelix (Plenaxis Depot®);aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb(Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®);altretamine (Hexylen®); amifostine (Ethyol®); anastrozole (Arimidex®);arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine(Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®);bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib(Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®);calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin(Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®);carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib(Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin(Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®);cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (CytoxanInjection®); cyclophosphamide (Cytoxan Tablet®); cytarabine(Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®);daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin(Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukindiftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®);doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®);doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®);DROMOSTANOLONE PROPIONATE (DROMOSTANOLONE®); DROMOSTANOLONE PROPIONATE(MASTERONE INJECTION®); Elliott's B Solution (Elliott's B Solution®);epirubicin (Ellence®); Epoetin alfa (Epogen®); erlotinib (Tarceva®);estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide,VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®);floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®);fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib(Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®);histrelin acetate (Histrelin Implant®); hydroxyurea (Hydrea®);Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide(IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®);Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide(Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®,Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®);lomustine, CCNU (CeeBU®); mechlorethamine, nitrogen mustard(Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®);mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (MesnexTabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C(Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®);nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®);Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®);paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-boundparticles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®);pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®);Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin(Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®);porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine(Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim(Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin(Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen(Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®);testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa(Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab(Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab(Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (UracilMustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®);vincristine (Oncovin®); vinorelbine (Navelbine®); vinorelbine(Navelbine®); zoledronate (Zometa®); and zoledronic acid (Zometa®).

The use of all of these approaches in combination with the4-carboxybenzylamino compounds described herein are within the scope ofthe present invention.

Dosages and Dosing Schedules

The dosage regimen utilizing the 4-carboxybenzylamino derivatives of thepresent invention can be selected in accordance with a variety offactors including type, species, age, weight, sex and the type of cancerbeing treated; the severity (i.e., stage) of the disease to be treated;the route of administration; the renal and hepatic function of thepatient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to treat, forexample, to prevent, inhibit (fully or partially) or arrest the progressof the disease.

For oral administration, suitable daily dosages are for example betweenabout 2-4000 mg administered orally once-daily, twice-daily or threetimes-daily, continuous (every day) or intermittently (e.g., 3-5 days aweek). For example, when used to treat the desired disease, the dose ofthe 4-carboxybenzylamino compound can range between about 2 mg to about2000 mg per day.

The 4-carboxybenzylamino derivative is administered once daily (QD), ordivided into multiple daily doses such as twice daily (BID), and threetimes daily (TID). For administration once a day, a suitably preparedmedicament would therefore contain all of the needed daily dose. Foradministration twice a day, a suitably prepared medicament wouldtherefore contain half of the needed daily dose. For administrationthree times a day, a suitably prepared medicament would thereforecontain one third of the needed daily dose.

In addition, the administration can be continuous, i.e., every day, orintermittently. The terms “intermittent” or “intermittently” as usedherein means stopping and starting at either regular or irregularintervals. For example, intermittent administration of an HDAC inhibitormay be administration one to six days per week or it may meanadministration in cycles (e.g., daily administration for two to eightconsecutive weeks, then a rest period with no administration for up toone week) or it may mean administration on alternate days.

Typically, an intravenous formulation may be prepared which contains aconcentration of the 4-carboxybenzylamino derivative of between about1.0 mg/mL to about 10 mg/mL. In one example, a sufficient volume ofintravenous formulation can be administered to a patient in a day suchthat the total dose for the day is between about 1 and about 1500 mg/m².

Subcutaneous formulations, preferably prepared according to procedureswell known in the art at a pH in the range between about 5 and about 12,also include suitable buffers and isotonicity agents, as describedbelow. They can be formulated to deliver a daily dose of HDAC inhibitorin one or more daily subcutaneous administrations, e.g., one, two orthree times each day.

The compounds can also be administered in intranasal form via topicaluse of suitable intranasal vehicles, or via transdermal routes, usingthose forms of transdermal skin patches well known to those of ordinaryskill in that art. To be administered in the form of a transdermaldelivery system, the dosage administration will, or course, becontinuous rather than intermittent throughout the dosage regime.

It should be apparent to a person skilled in the art that the variousmodes of administration, dosages and dosing schedules described hereinmerely set forth specific embodiments and should not be construed aslimiting the broad scope of the invention. Any permutations, variationsand combinations of the dosages and dosing schedules are included withinthe scope of the present invention.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Pharmaceutical Compositions

The compounds of the invention, and derivatives, fragments, analogs,homologs pharmaceutically acceptable salts or hydrate thereof, can beincorporated into pharmaceutical compositions suitable for oraladministration, together with a pharmaceutically acceptable carrier orexcipient. Such compositions typically comprise a therapeuticallyeffective amount of any of the compounds above, and a pharmaceuticallyacceptable carrier. In one embodiment, the effective amount is an amounteffective to selectively induce terminal differentiation of suitableneoplastic cells and less than an amount which causes toxicity in apatient.

Any inert excipient that is commonly used as a carrier or diluent may beused in the formulations of the present invention, such as for example,a gum, a starch, a sugar, a cellulosic material, an acrylate, ormixtures thereof. In one embodiment, the diluent is microcrystallinecellulose. The compositions may further comprise a disintegrating agent(e.g., croscarmellose sodium) and a lubricant (e.g., magnesiumstearate), and in addition may comprise one or more additives selectedfrom a binder, a buffer, a protease inhibitor, a surfactant, asolubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, aviscosity increasing agent, a sweetener, a film forming agent, or anycombination thereof. Furthermore, the compositions of the presentinvention may be in the form of controlled release or immediate releaseformulations.

In one embodiment, the pharmaceutical compositions are administeredorally, and are thus formulated in a form suitable for oraladministration, i.e., as a solid or a liquid preparation. Suitable solidoral formulations include tablets, capsules, pills, granules, pelletsand the like. Suitable liquid oral formulations include solutions,suspensions, dispersions, emulsions, oils and the like. In oneembodiment of the present invention, the composition is formulated in acapsule. In accordance with this embodiment, the compositions of thepresent invention comprise in addition to the 4-carboxybenzylaminoderivative active compound and the inert carrier or diluent, a hardgelatin capsule.

As used herein, “pharmaceutically acceptable carrier” is intended toinclude any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration, such as sterilepyrogen-free water. Suitable carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, a standard referencetext in the field, which is incorporated herein by reference. Examplesof such carriers or diluents include, but are not limited to, water,saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.,microcrystalline cellulose), an acrylate (e.g., polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil. Solutions or suspensions can also include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

In addition, the compositions may further comprise binders (e.g.,acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),disintegrating agents (e.g., cornstarch, potato starch, alginic acid,silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodiumstarch glycolate, Primogel), buffers (e.g., tris-HCl, acetate,phosphate) of various pH and ionic strength, additives such as albuminor gelatin to prevent absorption to surfaces, detergents (e.g., Tween20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors,surfactants (e.g., sodium lauryl sulfate), permeation enhancers,solubilizing agents (e.g., glycerol, polyethylene glycerol), a glidant(e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid,sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g.,hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosityincreasing agents (e.g., carbomer, colloidal silicon dioxide, ethylcellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citricacid), flavoring agents (e.g., peppermint, methyl salicylate, or orangeflavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens),lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol,sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

In one embodiment, oral compositions in dosage unit form are formulatedfor ease of administration and uniformity of dosage. Dosage unit form asused herein refers to physically discrete units suited as unitarydosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved, and the limitations inherent in the art ofcompounding such an active compound for the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

The compounds of the present invention may be administered intravenouslyon the first day of treatment, with oral administration on the secondday and all consecutive days thereafter.

The compounds of the present invention may be administered for thepurpose of preventing disease progression or stabilizing tumor growth.

The preparation of pharmaceutical compositions that contain an activecomponent is well understood in the art, for example, by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients that are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the active agents are mixed with additives customary forthis purpose, such as vehicles, stabilizers, or inert diluents, andconverted by customary methods into suitable forms for administration,such as tablets, coated tablets, hard or soft gelatin capsules, aqueous,alcoholic or oily solutions and the like as detailed above.

The amount of the compound administered to the patient is less than anamount that would cause unmanageable toxicity in the patient. In thecertain embodiments, the amount of the compound that is administered tothe patient is less than the amount that causes a concentration of thecompound in the patient's plasma to equal or exceed the toxic level ofthe compound. In one embodiment, the concentration of the compound inthe patient's plasma is maintained at about 10 nM. In anotherembodiment, the concentration of the compound in the patient's plasma ismaintained at about 25 nM. In another embodiment, the concentration ofthe compound in the patient's plasma is maintained at about 50 nM. Inanother embodiment, the concentration of the compound in the patient'splasma is maintained at about 100 nM. In another embodiment, theconcentration of the compound in the patient's plasma is maintained atabout 500 nM. In another embodiment, the concentration of the compoundin the patient's plasma is maintained at about 1000 nM. In anotherembodiment, the concentration of the compound in the patient's plasma ismaintained at about 2500 nM. In another embodiment, the concentration ofthe compound in the patient's plasma is maintained at about 5000 nM. Theoptimal amount of the compound that should be administered to thepatient in the practice of the present invention will depend on theparticular compound used and the type of cancer being treated.

The instant invention also includes a pharmaceutical composition usefulfor treating or preventing cancer that comprises a therapeuticallyeffective amount of a compound of Formula I and a second compoundselected from: an estrogen receptor modulator, an androgen receptormodulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent,an antiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, aPPAR-δ agonist, an inhibitor of cell proliferation and survivalsignaling, a bisphosphonate, an aromatase inhibitor, an siRNAtherapeutic, γ-secretase inhibitors, agents that interfere with receptortyrosine kinases (RTKs) and an agent that interferes with a cell cyclecheckpoint.

In Vitro Methods:

The present invention also provides methods of using the4-carboxybenzylamino derivatives of the present invention for inducingterminal differentiation, cell growth arrest and/or apoptosis ofneoplastic cells thereby inhibiting the proliferation of such cells. Themethods can be practiced in vivo or in vitro.

In one embodiment, the present invention provides in vitro methods forselectively inducing terminal differentiation, cell growth arrest and/orapoptosis of neoplastic cells, thereby inhibiting proliferation of suchcells, by contacting the cells with an effective amount of any one ormore of the 4-carboxybenzylamino derivatives described herein.

In a particular embodiment, the present invention relates to an in vitromethod of selectively inducing terminal differentiation of neoplasticcells and thereby inhibiting proliferation of such cells. The methodcomprises contacting the cells under suitable conditions with aneffective amount of one or more of the 4-carboxybenzylamino compoundsdescribed herein.

In another embodiment, the invention relates to an in vitro method ofselectively inducing cell growth arrest of neoplastic cells and therebyinhibiting proliferation of such cells. The method comprises contactingthe cells under suitable conditions with an effective amount of one ormore of the 4-carboxybenzylamino compounds described herein.

In another embodiment, the invention relates to an in vitro method ofselectively inducing apoptosis of neoplastic cells and therebyinhibiting proliferation of such cells. The method comprises contactingthe cells under suitable conditions with an effective amount of one ormore of the 4-carboxybenzylamino compounds described herein.

In another embodiment, the invention relates to an in vitro method ofinducing terminal differentiation of tumor cells in a tumor comprisingcontacting the cells with an effective amount of any one or more of the4-carboxybenzylamino compounds described herein.

Although the methods of the present invention can be practiced in vitro,it is contemplated that the preferred embodiment for the methods ofselectively inducing terminal differentiation, cell growth arrest and/orapoptosis of neoplastic cells, and of inhibiting HDAC will comprisecontacting the cells in vivo, i.e., by administering the compounds to asubject harboring neoplastic cells or tumor cells in need of treatment.

Thus, the present invention provides in vivo methods for selectivelyinducing terminal differentiation, cell growth arrest and/or apoptosisof neoplastic cells in a subject, thereby inhibiting proliferation ofsuch cells in the subject, by administering to the subject an effectiveamount of any one or more of the 4-carboxybenzylamino derivativesdescribed herein.

In a particular embodiment, the present invention relates to a method ofselectively inducing terminal differentiation of neoplastic cells andthereby inhibiting proliferation of such cells in a subject. The methodcomprises administering to the subject an effective amount of one ormore of the 4-carboxybenzylamino derivatives described herein.

In another embodiment, the invention relates to a method of selectivelyinducing cell growth arrest of neoplastic cells and thereby inhibitingproliferation of such cells in a subject. The method comprisesadministering to the subject an effective amount of one or more of the4-carboxybenzylamino derivatives described herein.

In another embodiment, the invention relates to a method of selectivelyinducing apoptosis of neoplastic cells and thereby inhibitingproliferation of such cells in a subject. The method comprisesadministering to the subject an effective amount of one or more of the4-carboxybenzylamino derivatives described herein.

In another embodiment, the invention relates to a method of treating apatient having a tumor characterized by proliferation of neoplasticcells. The method comprises administering to the patient one or more ofthe 4-carboxybenzylamino derivatives described herein. The amount ofcompound is effective to selectively induce terminal differentiation,induce cell growth arrest and/or induce apoptosis of such neoplasticcells and thereby inhibit their proliferation.

The invention is illustrated in the examples in the Experimental DetailsSection that follows. This section is set forth to aid in anunderstanding of the invention but is not intended to, and should not beconstrued to limit in any way the invention as set forth in the claimswhich follow thereafter.

EXPERIMENTAL DETAILS SECTION Example 1 Synthesis

The compounds of the present invention were prepared by the generalmethods outlined in the synthetic schemes below, as exemplified below.

A. Compounds Synthesized According to Scheme 1

4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]benzoic acid

A solution of CDI (107 g, 662 mmol) in dry THF (700 mL) was treated witha solution of pyridin-3-ylmethanol (72.2 g, 662 mmol) in THF (300 mL)dropwise over 10 minutes. The resulting solution was stirred for 1.25hours and then added dropwise over 15 minutes to a water bath cooledsuspension of 4-(aminomethyl)benzoic acid (100 g, 662 mmol), Et₃N (92mL, 662 mmol) and DBU (100 mL, 662 mmol) in dry THF (1400 mL). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo and the residue suspended in water(2500 mL), cooled in an ice-water bath and the pH adjusted to 5 with 6 NHCl (˜300 mL). The precipitate was collected by filtration, washed withcold MeOH and dried to give4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]benzoic acid as awhite solid. ¹H NMR (d6-DMSO, 600 MHz) δ 12.82 (br s, 1H), 8.56 (d,J=1.8 Hz, 1H), 8.51 (dd, J=4.8 and 1.8 Hz, 1H), 7.93 (t, J=6.3 Hz, 1H),7.87 (d, J=8.4 Hz, 2H), 7.76 (t, J=8.4 Hz, 1H), 7.38 (dd, J=7.2 and 4.8Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 4.25 (d, J=6.3 Hz, 1H).

1,1-dimethylethyl{3-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate

4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]benzoic acid 10.3 g,36 mmol), HOBt (6.61 g, 43.2 mmol) and EDC (8.28 g, 43.2 mmol) werestirred in DMF (257 mL) for 10 minutes. 1,1-dimethylethyl(3-aminobiphenyl-4-yl)carbamate (13.3 g, 46.8 mmol) was added and thereaction mixture stirred at 60° C. overnight. The solvent was removed invacuo, H₂O was added and the products extracted into EtOAc (×2). Thecombined organic extracts were dried over MgSO₄ and concentrated invacuo. The residue was triturated in DCM to give1,1-dimethylethyl[2-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]-4-(2-thienyl)phenyl]carbamateas an off-white solid. Purification of the mother liquor by MPLC(80-100% EtOAc-hexanes) gave a second batch of product that wasspectroscopically consistent with the first batch. ¹H NMR (d6-DMSO, 600MHz) δ 9.69 (s, 1H), 8.75 (s, 1H), 8.57 (s, 1H), 8.51 (d, J=4.2 Hz, 1H),7.97 (t, J=6.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.83 (s, 1H), 7.77 (d,J=7.8 Hz, 1H), 7.62 (m, 3H), 7.50 (dd, J=7.8 and 1.8 Hz, 1H), 7.44 (t,J=7.8 Hz, 2H), 7.39 (m, 3H), 7.33 (t, J=7.2 Hz, 1H), 5.08 (s, 2H), 4.27(d, J=6.0 Hz, 2H), 1.44 (s, 9H).

Example 1Pyridin-3-ylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate

1,1-dimethylethyl[2-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]-4-(2-thienyl)phenyl]carbamate(10.5 g, 19 mmol) was taken up in DCM (208 mL)/TFA (41.7 mL). After 1hour, the solvent was removed in vacuo, saturated NaHCO₃ was added andthe products extracted into EtOAc (×2). The combined organic extractswere washed with brine, dried over MgSO₄ and concentrated in vacuo togivepyridin-3-ylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamateas a tan solid. ¹H NMR (d6-DMSO, 600 MHz) δ 9.69 (s, 1H), 8.57 (s, 1H),8.51 (dd, J=4.8 and 1.8 Hz, 1H), 7.94 (m, 3H), 7.77 (d, J=7.8 Hz, 1H),7.53 (d, J=7.8 Hz, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.37 (m, 5H), 7.31 (dd,J=8.4 and 1.8 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H),5.08 (br s, 4H), 4.26 (d, J=6.0 Hz, 2H). MS: cal'd 453 (MH⁺), exp 453(MH⁺).

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 1 Example # Structure Name MS Salt forms 2

methyl 4′-amino-3′- [({4-[({[(pyridin-3- ylmethyl)oxy]car-bonyl}amino)meth- yl]phenyl}carbonyl)a- mino]biphenyl-4- carboxylatecal'd 511 (MH⁺), exp 511 (MH⁺) TFA 3

pyridin-3-ylmethyl [(4-{[(2-amino-5- pyridin-3- ylphenyl)amino]car-bonyl}phenyl)meth- yl]carbamate cal'd 454 (MH⁺), exp 454 (MH⁺) TFA 4

pyridin-3-ylmethyl {[4-({[2-amino-5- (3-thienyl)phenyl]a-mino}carbonyl)phen- yl]methyl}carbamate cal'd 459 (MH⁺), exp 459 (MH⁺)Free base 5

pyridin-3-ylmethyl [(4-{[(4- hydroxybiphenyl-3- yl)amino]carbon-yl}phenyl)methyl]car- bamate cal'd 454 (MH⁺), exp 454 (MH⁺) TFA 6

pyridin-3-ylmethyl [(4-{[(2-hydroxy-5- pyridin-3- ylphenyl)amino]car-bonyl}phenyl)meth- yl]carbamate cal'd 455 (MH⁺), exp 455 (MH⁺) TFA 7

1,1-dimethylethyl [(4-{[(4- hydroxybiphenyl-3- yl)amino]carbon-yl}phenyl)methyl]car- bamate cal'd 419 (MH⁺), exp 419 (MH⁺) Free base 8

4-(aminomethyl)-N- (4-hydroxybiphenyl- 3-yl)benzamide cal'd 319 (MH⁺),exp 319 (MH⁺) TFA

B. Compounds Synthesized According to Scheme 2

1,1-dimethylethyl[3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate

4-(chloromethyl)benzoyl chloride (12 g, 63.5 mmol) was dissolved in THF(120 mL) and a solution of 1,1-dimethylethyl(3-aminobiphenyl-4-yl)carbamate (19.86 g, 69.8 mmol) and DIPEA (12.2 mL,69.8 mmol) in THF (300 mL) was added dropwise at room temperature. Afterstirring for 1 hour, saturated NaHCO₃ was added and the productsextracted into EtOAc (×2). The combined organic extracts were dried overMgSO₄ and concentrated in vacuo. The residue was triturated in Et₂O togive1,1-dimethylethyl[3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamateas a white solid. ¹H NMR (d6-DMSO, 600 MHz) δ 9.92 (s, 1H), 8.75 (s,1H), 7.97 (d, J=8.4 Hz, 2H), 7.83 (s, 1H), 7.63 (m, 3H), 7.59 (d, J=8.4Hz, 2H), 7.50 (dd, J=8.4 and 1.8 Hz, 1H), 7.44 (t, J=7.2 Hz, 2H), 7.33(t, J=7.2 Hz, 1H), 4.84 (s, 2H), 1.44 (s, 9H).

1,1-dimethylethyl[2-({[4-(chloromethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate

Prepared according to the procedure described above.1,1-dimethylethyl[2-({[4-(chloromethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamatewas obtained as a beige solid. ¹H NMR (d6-DMSO, 600 MHz) δ 9.91 (s, 1H),8.72 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.78 (d, J=1.8 Hz, 1H), 7.58 (m,3H), 7.49 (m, 2H), 7.42 (dd, J=3.6 and 1.2 Hz, 1H), 7.10 (dd, J=5.4 and3.6 Hz, 1H), 4.83 (s, 2H), 1.42 (s, 9H).

1,1-dimethylethyl{3-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate

1,1-dimethylethyl[3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate(20 g, 45.8 mmol), potassium phthalimide (9.33 g, 50.4 mmol) andpotassium iodide (1.52 g, 9.15 mmol) were stirred in DMF (81 mL) at 50°C. overnight. Room temperature was attained, H₂O was added and theproducts extracted into EtOAc (×2). The combined organic extracts werewashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was triturated in MeOH to give 1,1-dimethylethyl{3-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamateas a pale yellow solid.

1,1-dimethylethyl[2-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]-4-(2-thienyl)phenyl]carbamate

Prepared according to the procedure described above.1,1-dimethylethyl[2-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]-4-(2-thienyl)phenyl]carbamatewas obtained as a pale yellow solid.

1,1-dimethylethyl[3-({[4-(aminomethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate

1,1-dimethylethyl{3-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate(17 g, 31 mmol) and hydrazine hydrate (3.01 mL, 62.1 mmol) were stirredin refluxing EtOH (135 mL) for 5 hours. Room temperature was attainedand the white precipitate removed by filtration and washed with EtOH.The filtrate was concentrated in vacuo and purified by MPLC (10%[MeOH+1% NH₄OH]-DCM) to give1,1-dimethylethyl[3-({[4-(aminomethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamateas a white solid. ¹H NMR (d6-DMSO, 600 MHz) δ 9.86 (s, 1H), 8.77 (s,1H), 7.90 (d, J=7.8 Hz, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.62 (m, 3H), 7.49(m, 3H), 7.44 (t, J=7.5 Hz, 2H), 7.33 (t, J=7.5 Hz, 1H), 3.79 (s, 2H),1.45 (s, 9H).

1,1-dimethylethyl[2-({[4-(aminomethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate

Prepared according to the procedure described above.1,1-dimethylethyl[2-({[4-(aminomethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamatewas obtained as a white solid. ¹H NMR (d6-DMSO, 600 mHz) δ 9.86 (s, 1H),8.73 (s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.81 (d, J=1.8 Hz, 1H), 7.57 (d,J=8.4 Hz, 1H), 7.49 (m, 4H), 7.43 (dd, J=3.6 and 1.2 Hz, 1H), 7.11 (dd,J=5.4 and 3.6 Hz, 1H), 3.78 (s, 2H), 1.43 (s, 9H).

1,1-dimethylethyl[3-({[4-({[(methyloxy)carbonyl]amino}methyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate

1,1-dimethylethyl[3-({[4-(aminomethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate(0.404 g, 0.967 mmol) and DIPEA (0.22 mL, 1.257 mmol) were taken up inDCM (10 mL) and methyl chloroformate (82 μL, 1.064 mmol) was addeddropwise. After stirring for 30 minutes, water was added and theproducts extracted into DCM (×3). The combined organic extracts werewashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was triturated in DCM to give1,1-dimethylethyl[3-({[4-({[(methyloxy)carbonyl]amino}methyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamateas a beige solid. ¹H NMR (d6-DMSO, 600 MHz) δ 9.86 (s, 1H), 8.73 (s,1H), 7.90 (d, J=8.4 Hz, 2H), 7.81 (d, J=1.8 Hz, 1H), 7.75 (t, J=6.0 Hz,1H), 7.61 (m, 3H), 7.48 (dd, J=9.0 and 3.6 Hz, 1H), 7.43 (t, J=8.1 Hz,2H), 7.38 (d, J=8.4 Hz, 2H), 7.32 (t, J=7.5 Hz, 1H), 4.23 (d, J=6.0 Hz,2H), 3.53 (s, 3H), 1.42 (s, 9H).

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 2 Example # Structure Name MS Salt forms 9

methyl [(4-{[(4- aminobiphenyl-3- yl)amino]carbon- yl}phenyl)methyl]car-bamate cal'd 376 (MH⁺), exp 376 (MH⁺) Free base 10

ethyl [(4-{[(4- aminobiphenyl-3- yl)amino]carbon- yl}phenyl)methyl]car-bamate cal'd 390 (MH⁺), exp 390 (MH⁺) Free base 11

1-methylethyl [(4- {[(4- aminobiphenyl-3- yl)amino]carbon-yl}phenyl)methyl]car- bamate cal'd 404 (MH⁺), exp 404 (MH⁺) Free base 12

propyl [(4-{[(4- aminobiphenyl-3- yl)amino]carbon- yl}phenyl)methyl]car-bamate cal'd 404 (MH⁺), exp 404 (MH⁺) Free base 13

2-methylpropyl [(4- {[(4- aminobiphenyl-3- yl)amino]carbon-yl}phenyl)methyl]car- bamate cal'd 418 (MH⁺), exp 418 (MH⁺) Free base 14

phenyl [(4-{[(4- aminobiphenyl-3- yl)amino]carbon- yl}phenyl)methyl]car-bamate cal'd 438 (MH⁺), exp 438 (MH⁺) Free base 15

phenylmethyl [(4- {[(4- aminobiphenyl-3- yl)amino]carbon-yl}phenyl)methyl]car- bamate cal'd 452 (MH⁺), exp 452 (MH⁺) Free base 16

ethyl {[4-({[2- amino-5-(2- thienyl)phenyl]a- mino}carbonyl)phen-yl]methyl}carbamate cal'd 396 (MH⁺), exp 396 (MH⁺) Free base 17

methyl {[4-({[2- amino-5-(2- thienyl)phenyl]a- mino}carbonyl)phen-yl]methyl}carbamate cal'd 382 (MH⁺), exp 382 (MH⁺) Free base 18

1-methylethyl {[4- ({[2-amino-5-(2- thienyl)phenyl]a-mino}carbonyl)phen- yl]methyl}carbamate cal'd 410 (MH⁺), exp 410 (MH⁺)Free base 19

propyl {[4-({[2- amino-5-(2- thienyl)phenyl]a- mino}carbonyl)phen-yl]methyl}carbamate cal'd 410 (MH⁺), exp 410 (MH⁺) Free base 20

2-methylpropyl {[4-({[2-amino-5- (2-thienyl)phenyl]a-mino}carbonyl)phen- yl]methyl}carbamate cal'd 424 (MH⁺), exp 424 (MH⁺)Free base 21

phenyl {[4-({[2- amino-5-(2- thienyl)phenyl]a- mino}carbonyl)phen-yl]methyl}carbamate cal'd 444 (MH⁺), exp 444 (MH⁺) Free base 22

phenylmethyl {[4- ({[2-amino-5-(2- thienyl)phenyl]a- mino}carbonyl)phen-yl]methyl}carbamate cal'd 458 (MH⁺), exp 458 (MH⁺) Free base 23

4- [(acetylamino)meth- yl]-N-(4- aminobiphenyl-3- yl)benzamide cal'd 360(MH⁺), exp 360 (MH⁺) Free base 24

N-(4- aminobiphenyl-3- yl)-4- [(propanoylami- no)methyl]benzamide cal'd374 (MH⁺), exp 374 (MH⁺) Free base 25

N-(4- aminobiphenyl-3- yl)-4- [(butanoylami- no)methyl]benzamide cal'd388 (MH⁺), exp 388 (MH⁺) Free base 26

N-(4- aminobiphenyl-3- yl)-4- {[(cyclopropylcar- bonyl)amino]meth-yl}benzamide cal'd 386 (MH⁺), exp 386 (MH⁺) Free base 27

N-(4- aminobiphenyl-3- yl)-4-{[(2- methylpropanoyl)a- mino]methyl}benza-mide cal'd 388 (MH⁺), exp 388 (MH⁺) Free base 28

N-(4- aminobiphenyl-3- yl)-4-{[(2,2- dimethylpropanoyl)a-mino]methyl}benza- mide cal'd 402 (MH⁺), exp 402 (MH⁺) Free base 29

N-(4- aminobiphenyl-3- yl)-4-{[(3- methylbutanoyl)a- mino]methyl}benza-mide cal'd 402 (MH⁺), exp 402 (MH⁺) Free base 30

N-(4- aminobiphenyl-3- yl)-4- {[(cyclobutylcarbon- yl)amino]meth-yl}benzamide cal'd 400 (MH⁺), exp 400 (MH⁺) Free base 31

N-(4- aminobiphenyl-3- yl)-4-{[(3- phenylpropanoyl)a- mino]methyl}benza-mide cal'd 450 (MH⁺), exp 450 (MH⁺) Free base 32

N-(4- aminobiphenyl-3- yl)-4- {[(cyclohexylcarbon- yl)amino]meth-yl}benzamide cal'd 428 (MH⁺), exp 428 (MH⁺) Free base 33

N-(4- aminobiphenyl-3- yl)4- {[(cyclopentylcarbon- yl)amino]meth-yl}benzamide cal'd 414 (MH⁺), exp 414 (MH⁺) Free base 34

N-(4- aminobiphenyl-3- yl)-4- {[(phenylacetyl)a- mino]methyl}benza- midecal'd 436 (MH⁺), exp 436 (MH⁺) Free base 35

N-(4- aminobiphenyl-3- yl)-4- {[(phenylcarbonyl)a- mino]methyl}benza-mide cal'd 422 (MH⁺), exp 422 (MH⁺) Free base 36

4- [(acetylamino)meth- yl]-N-[2-amino-5-(2- thienyl)phenyl]benza- midecal'd 366 (MH⁺), exp 366 (MH⁺) Free base 37

N-[2-amino-5-(2- thienyl)phenyl]-4- [(propanoylami- no)methyl]benzamidecal'd 380 (MH⁺), exp 380 (MH⁺) Free base 38

N-[2-amino-5-(2- thienyl)phenyl]-4- [(butanoylami- no)methyl]benzamidecal'd 394 (MH⁺), exp 394 (MH⁺) Free base 39

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(cyclopropylcar- bonyl)amino]meth-yl}benzamide cal'd 392 (MH⁺), exp 392 (MH⁺) Free base 40

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(2- methylpropanoyl)a-mino]methyl}benza- mide cal'd 394 (MH⁺), exp 394 (MH⁺) Free base 41

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(2,2- dimethylpropanoyl)a-mino]methyl}benza- mide cal'd 408 (MH⁺), exp 408 (MH⁺) Free base 42

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(3- methylbutanoyl)a-mino]methyl}benza- mide cal'd 408 (MH⁺), exp 408 (MH⁺) Free base 43

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(cyclobutylcarbon- yl)amino]meth-yl}benzamide cal'd 406 (MH⁺), exp 406 (MH⁺) Free base 44

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(3- phenylpropanoyl)a-mino]methyl}benza- mide cal'd 456 (MH⁺), exp 456 (MH⁺) Free base 45

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(cyclohexylcarbon- yl)amino]meth-yl}benzamide cal'd 434 (MH⁺), exp 434 (MH⁺) Free base 46

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(cyclopentylcarbon- yl)amino]meth-yl}benzamide cal'd 420 (MH⁺), exp 420 (MH⁺) Free base 47

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(phenylacetyl)a-mino]methyl}benza- mide cal'd 442 (MH⁺), exp 442 (MH⁺) Free base 48

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(phenylcarbonyl)a-mino]methyl}benza- mide cal'd 428 (MH⁺), exp 428 (MH⁺) Free base

C. Compounds Synthesized According to Scheme 3

1,1-dimethylethyl[2-{[(4-{[(pyridin-3-ylacetyl)amino]methyl}phenyl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate

A suspension of1,1-dimethylethyl[3-({[4-(aminomethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate(100 mg, 0.23 mmol), pyridin-3-ylacetic acid hydrochloride (44 mg, 0.26mmol), DIPEA (0.2 mL, 1 mmol) and HATU (110 mg, 0.28 mmol) in 10 mL ofDCM was stirred at room temperature for 12 hours. Then 100 mL of DCM wasadded the reaction mixture and washed with 10% NaHCO₃ and brine, theorganic layer was dried over Na₂SO₄. The solvent was removed in vacuoand the residue was purified by preparative TLC to give1,1-dimethylethyl[2-{[(4-{[(pyridin-3-ylacetyl)amino]methyl}phenyl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate.

Example 49N-[2-amino-5-(2-thienyl)phenyl]-4-{[(pyridin-3-ylacetyl)amino]methyl}benzamide

1,1-dimethylethyl[2-{[(4-{[(pyridin-3-ylacetyl)amino]methyl}phenyl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamatewas stirred in 10 mL of TFA/DCM (1:1 v/v) for 2 hours. Then 20 mL ofsaturated NaHCO₃ was added to the reaction mixture and the resultedsolution was stirred for 20 minutes, 50 mL of DCM was added to thereaction mixture and the organic layer was separated and the aqueousphase was extracted with DCM (50 mL×2), the combined organic layers werewashed with brine, dried over Na₂SO₄, the solvent was removed and theresidue was washed with 10 mL of anhydrous ethyl ether, filtered to giveN-[2-amino-5-(2-thienyl)phenyl]-4-{[(pyridin-3-ylacetyl)amino]methyl}benzamideas a beige solid. ¹H NMR (MeOD, 600 MHz) δ 8.49 (s, 1H), 8.43 (d, J=5.4Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.40 (m, 5H),7.21 (m, 2H), 7.02 (m, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.48 (s, 2H), 3.64(s, 2H). MS: cal'd 443 (MH⁺), exp 443 (MH⁺).

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 3 Example # Structure Name MS Salt forms 50

N-(4-aminobiphenyl- 3-yl)-4-{[(pyridin-2- ylacetyl)amino]meth-yl}benzamide cal'd 437 (MH⁺), exp 437 (MH⁺) Free base 51

N-(4-aminobiphenyl- 3-yl)-4-([(pyridin-3- ylacetyl)amino]meth-yl}benzamide cal'd 437 (MH⁺), exp 437 (MH⁺) Free base 52

N-(4-aminobiphenyl- 3-yl)-4-{[(pyridin-4- ylacetyl)amino]meth-yl}benzamide cal'd 437 (MH⁺), exp 437 (MH⁺) Free base 53

N-(4-aminobiphenyl- 3-yl)-4-{[(3-pyridin- 3-ylpropanoyl)ami-no]methyl}benzamide cal'd 451 (MH⁺), exp 451 (MH⁺) Free base 54

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(pyridin-2- ylacetyl)amino]meth-yl}benzamide cal'd 443 (MH⁺), exp 443 (MH⁺) Free base 55

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(pyridin-4- ylacetyl)amino]meth-yl}benzamide cal'd 443 (MH⁺), exp 443 (MH⁺) Free base 56

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(3-pyridin-3- ylpropanoyl)ami-no]methyl}benzamide cal'd 457 (MH⁺), exp 457 (MH⁺) Free base 57

(2S)-N-[4-({[2-amino- 5-(2- thienyl)phenyl]ami- no}carbonyl)benzyl]pyr-rolidine-2- carboxamide cal'd 421 (MH⁺), exp 421 (MH⁺) Free base 58

(2S)-N-(4-{[(4- aminobiphenyl-3- yl)amino]carbon- yl}benzyl)pyrrolidine-2-carboxamide cal'd 415 (MH⁺), exp 415 (MH⁺) Free base

D. Compounds Synthesized According to Scheme 4

1,1-dimethylethyl{3-[({4-[({[(pyridin-2-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate

Prepared from1,1-dimethylethyl[3-({[4-(aminomethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamateaccording to the procedure described in section A. 1,1-dimethylethyl{3-[({4-[({[(pyridin-2-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamatewas obtained as a tan solid. MS: cal'd 553 (MH⁺), exp 553 (MH⁺).

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 4 Example # Structure Name MS Salt forms 59

pyridin-2-ylmethyl [(4-{[(4- aminobiphenyl-3- yl)amino]carbon-yl}phenyl)methyl]car- bamate cal'd 453 (MH⁺), exp 453 (MH⁺) Free base

E. Compounds Synthesized According to Scheme 5

Methyl 4-({[(dimethylamino)sulfonyl]amino}methyl)benzoate

4-(aminomethyl)benzoic acid methyl ester (0.2676 g, 1.620 mmol) wasdissolved in dichloromethane (15 ml). DMAP (0.0248 g, 0.203 mmol) andDIEA (0.35 ml, 2.004 mmol) were added. The solution was cooled to 0° C.Dimethylsulfamoyl chloride (0.18 ml, 1.676 mmol) was added. The reactionwas allowed to stir until completion. The reaction was diluted with DCMand washed with aqueous sodium hydrogen carbonate. The aqueous layer wasextracted with DCM two times. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The residue was purified bycolumn chromatography on silica gel, eluting with EtOAc/hexane (6-50%).MS: cal'd 273 (MH⁺), exp 273 (MH⁺).

4-({[(dimethylamino)sulfonyl]amino}methyl)benzoic acid

Methyl 4-({[(dimethylamino)sulfonyl]amino}methyl)benzoate (0.25 g, 0.918mmol) was dissolved in THF (5 ml). Potassium hydroxide (5 ml, 10.00mmol) was added. The reaction was heated to 50° C. for 3.5 h, untilreaction was complete as indicated by LCMS. Hydrochloric acid (5 ml, 2N)was added. The reaction was concentrated under reduced pressure. Theresulting material was dissolved in organic solvent DCM/MeOH and washedwith brine. The aqueous layer was extracted with DCM/MeOH two times. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. ¹H NMR (d6-DMSO, 600 MHz) δ 12.88 (s, 1H), 7.88 (d, J=8.5Hz, 2H), 7.76 (t, J=6.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 2H), 4.14 (d, J=6.5Hz, 2H), 2.59 (s, 6H). MS: cal'd 259 (MH⁺), exp 259 (MH⁺).

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 5 Example # Structure Name MS Salt forms 60

N-[2-amino-5-(2- thienyl)phenyl]-4- ({[(dimethylamino)sulfonyl]a-mino}methyl)benzamide cal'd 431 (MH⁺), exp 431 (MH⁺) Free base

F. Compounds Synthesized According to Scheme 6

Example 61N-(4-amino-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide

67 mg of FDMP stratospheres resin (loading 1.5 mmol/g) (0.10 mmol), 142mg (0.5 mmol) 1,1-dimethylethyl (3-aminobiphenyl-4-yl)carbamate, and 1ml of 5% AcOH in DCE was added to a scintillation vial and allowed toshake overnight at room temperature. 106 mg (0.5 mmol) of NaBH(OAc)₃ wasadded to the vial in 1 ml of 5% AcOH in DCE. The vial was capped andvented, and allowed to react for 3 days at room temperature. The resinwas washed with each of the following solvents 3× each and dried invacuo: DMF, MeOH, H₂O, MeOH, and DCM.

0.1 mmol of resin from the previous step was added to a scintillationvial along with 2 ml of DCM and 51 mg (0.4 mmol) of DIEA. The vial wasshaken for 1 minute and 38 mg (0.2 mmol) of 4-chloromethyl benzoylchloride was added. The vial was capped and vented, and allowed to reactovernight at room temperature. The resin was washed with each of thefollowing solvents 3× each and dried in vacuo: DCM, DMF, H₂O, MeOH, andDCM.

0.1 mmol of resin from the previous step was added to a scintillationvial along with 214 mg (1.0 mmol) of proton sponge, 45 mg (0.3 mmol) ofNaI, 45 mg (0.5 mmol) of 4-aminopyridine, and 2 ml of DMF. The resin waswashed with each of the following solvents three times each and dried invacuo: DMF, H₂O, MeOH, and DCM.

0.1 mmol of resin from the previous step was cleaved with 3 ml of 1:1DCM:TFA for 2 hours at room temperature. The filtrate was collected andpurified by HPLC to yieldN-(4-amino-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide as awhite solid. MS: cal'd 395 (MH⁺), exp 395 (MH⁺).

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 6 Example # Structure Name MS Salt forms 62

N-(4-amino-3- biphenylyl)-4- {[methyl(4- pyridinyl)amino]meth-yl}benzamide cal'd 409 (MH⁺), exp 409 (MH⁺) Free base 63

N-(4-amino-3- biphenylyl)-4-({[(1,5- dimethyl-1H-pyrazol- 4-yl)methyl]amino{meth- yl)benzamide cal'd 426 (MH⁺), exp 426 (MH⁺) Freebase 64

N-(4-amino-3- biphenylyl)-4- ({methyl[3- (methylamino)pro-pyl]amino}meth- yl)benzamide cal'd 403 (MH⁺), exp 403 (MH⁺) Free base 65

N-(4-amino-3- biphenylyl)-4- [(isobutylamino)meth- yl]benzamide cal'd374 (MH⁺), exp 374 (MH⁺) Free base 66

N-(4-amino-3- biphenylyl)-4-{[(2- methoxy-1- methylethyl)ami-no]methyl}benzamide cal'd 390 (MH⁺), exp 390 (MH⁺) Free base 67

N-(4-amino-2′-fluoro- 3-biphenylyl)-4-[(4- pyridinylamino)meth-yl]benzamide cal'd 413 (MH⁺), exp 413 (MH⁺) Free base 68

N-(4-amino-3′-fluoro- 3-biphenylyl)-4-[(4- pyridinylamino)meth-yl]benzamide cal'd 413 (MH⁺), exp 413 (MH⁺) Free base 69

N-[2-amino-5-(4- methyl-2- thienyl)phenyl]-4-[(4- pyridinylamino)meth-yl]benzamide cal'd 415 (MH⁺), exp 415 (MH⁺) Free base 70

N-[2-amino-5-(4- methyl-3- thienyl)phenyl]-4-[(4- pyridinylamino)meth-yl]benzamide cal'd 415 (MH⁺), exp 415 (MH⁺) Free base

G. Compounds Synthesized According to Scheme 7

Example 71N-(4-hydroxy-3-biphenylyl)-4-{[(2-phenylethyl)amino]methyl}benzamide

133 mg of benzyloxybenzylbromide resin (loading 0.75 mmol/g) (0.10mmol), 108 mg (0.5 mmol) of 2-nitro-4-phenyl phenol, 326 mg of cesiumcarbonate and 2 ml of DMF were added to a 2-5 ml microwave vial andmicrowaved at 140° C. for 10 minutes. The resin was filtered into afitted reaction tube and washed with each of the following solvents 3×each and dried in vacuo: DMF, H₂O, MeOH, and DCM.

The frit was closed and 2 ml of a 2M solution of SnCl₂ was added to 0.1mmol of resin from the previous step. The vial was sealed and shakenovernight at room temperature. The resin was washed with each of thefollowing solvents 3× each and dried in vacuo: DMF, Isopropanol, andDCM.

A stock solution of DMAP (98 mg, 0.8 mmol) and DIEA (35 ul, 0.2 mmol)was made in 2 ml of DCM. The stock solution was added to the resinfollowed by the addition of 198 mg 4-chloromethylbenzoyl chloride (1.0mmol) in 2 ml of DCM. The vial was sealed and shaken overnight at roomtemperature. The resin was washed with each of the following solventsthree times each and dried in vacuo: DMF, Isopropanol, and DCM.

A stock solution of proton sponge (150 mg, 0.7 mmol), NaI (31 mg, 0.21mmol) and phenethylamine (42 mg, 0.35 mmol) was made in 3 ml of DMF andadded to 0.1 mmol of resin from the previous step. The vial was sealedand allowed to react overnight at room temperature. The resin was washedwith each of the following solvents three times each and dried in vacuo:DMF, Isopropanol, and DCM.

0.1 mmol of resin from the previous step was cleaved with 3 ml of 1:1DCM:TFA for 2 hours at room temperature. The filtrate was collected andpurified by HPLC to yieldN-(4-hydroxy-3-biphenylyl)-4-{[(2-phenylethyl)amino]methyl}benzamide asa white solid. MS: cal'd 423 (MH⁺), exp 423 (MH⁺).

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 7 Example # Structure Name MS Salt forms 72

4-({[2-(4- bromophenyl)ethyl]a- mino}methyl)-N-{4- hydroxy-3-biphenylyl)benza- mide cal'd 501 (MH⁺), exp 501 (MH⁺) Free base 73

N-(4-hydroxy-3- biphenylyl)-4- [(isobutylamino)meth- yl]benzamide cal'd375 (MH⁺), exp 375 (MH⁺) Free base 74

N-(4-hydroxy-3- biphenylyl)-4-({[(4- methyl-2-phenyl-1,3- thiazol-5-yl)methyl]amino}meth- yl)benzamide cal'd 506 (MH⁺), exp 506 (MH⁺) Freebase 75

4-[(cyclopropyla- mino)methyl]-N-(4- hydroxy-3- biphenylyl)benzamidecal'd 359 (MH⁺), exp 359 (MH⁺) Free base 76

4-(anilinomethyl)-N- (4-hydroxy-3- biphenylyl)benzamide cal'd 395 (MH⁺),exp 395 (MH⁺) Free base 77

4-[(cyclopentyla- mino)methyl]-N-(4- hydroxy-3- biphenylyl)benzamidecal'd 387 (MH⁺), exp 387 (MH⁺) Free base 78

4-{[(cyclopropylmeth- yl)aminolmethyl}-N- (4-hydroxy-3-biphenylyl)benzamide cal'd 373 (MH⁺), exp 373 (MH⁺) Free base 79

N-(4-hydroxy-3- biphenylyl)-4-({[2- (1H-imidazol-4- yl)ethyl]amino}meth-yl)benzamide cal'd 412 (MH⁺), exp 412 (MH⁺) Free base 80

4-({[2- (dimethylamino)eth- yl]amino}methyl)-N- (4-hydroxy-3-biphenylyl)benzamide cal'd 390 (MH⁺), exp 390 (MH⁺) Free base 81

N-(4-hydroxy-3- biphenylyl)-4-{[(3- pyridinylmethyl)ami-no]methyl}benzamide cal'd 410 (MH⁺), exp 410 (MH⁺) Free base 82

N-(4-hydroxy-3- biphenylyl)-4-({[3- (1-pyrrolidinyl) propyl]amino}meth-yl)benzamide cal'd 430 (MH⁺), exp 430 (MH⁺) Free base 83

N-(4-hydroxy-3- biphenylyl)-4-(1- piperazinylmeth- yl)benzamide cal'd388 (MH⁺), exp 388 (MH⁺) Free base 84

N-(4-hydroxy-3- biphenylyl)-4-[(4- pyridinylamino)meth- yl]benzamidecal'd 396 (MH⁺), exp 396 (MH⁺) Free base 85

N-(4-hydroxy-3- biphenylyl)-4-(4- morpholinylmeth- yl)benzamide cal'd389 (MH⁺), exp 389 (MH⁺) Free base 86

N-(4-hydroxy-3- biphenylyl)-4-{[(3- isopropoxypropyl)a-mino]methyl}benza- mide cal'd 419 (MH⁺), exp 419 (MH⁺) Free base 87

N-(4-hydroxy-3- biphenylyl)-4-[(4- methyl-1- piperidinyl)meth-yl]benzamide cal'd 401 (MH⁺), exp 401 (MH⁺) Free base 88

4-{[benzyl(methyl)a- mino]methyl}-N-(4- hydroxy-3- biphenylyl)benzamidecal'd 423 (MH⁺), exp 423 (MH⁺) Free base 89

N-(4-hydroxy-3- biphenylyl)-4-{[(3- phenylpropyl)ami-no]methyl}benzamide cal'd 437 (MH⁺), exp 437 (MH⁺) Free base 90

4-(3,4-dihydro- 2(1H)- isoquinolinylmeth- yl)-N-(4-hydroxy-3-biphenylyl)benzamide cal'd 435 (MH⁺), exp 435 (MH⁺) Free base 91

N-(4-hydroxy-3- biphenylyl)-4-({[2- (isopropylamino)eth- yl]amino}meth-yl)benzamide cal'd 404 (MH⁺), exp 404 (MH⁺) Free base 92

N-(4-hydroxy-3- biphenylyl)-4-{[(3- methylbutyl)ami- no]methyl}benzamidecal'd 389 (MH⁺), exp 389 (MH⁺) Free base 93

N-(4-hydroxy-3- biphenylyl)-4- {[methyl(2- phenylethyl)ami-no]methyl}benzamide cal'd 437 (MH⁺), exp 437 (MH⁺) Free base 94

4- {[ethyl(methyl)ami- no]methyl}-N-(4- hydroxy-3- biphenylyl)benzamidecal'd 361 (MH⁺), exp 361 (MH⁺) Free base 95

4-(1,3-dihydro-2H- isoindol-2-ylmethyl)- N-(4-hydroxy-3-biphenylyl)benzamide cal'd 421 (MH⁺), exp 421 (MH⁺) Free base 96

N-(4-hydroxy-3- biphenylyl)-4-{[(2- phenoxyethyl)ami-no]methyl}benzamide cal'd 439 (MH⁺), exp 439 (MH⁺) Free base 97

4-{[(2- anilinoethyl)ami- no]methyl}-N-(4- hydroxy-3-biphenylyl)benzamide cal'd 438 (MH⁺), exp 438 (MH⁺) Free base 98

N-(4-hydroxy-3- biphenylyl)-4-{[(2- thienylmethyl)ami-no]methyl}benzamide cal'd 415 (MH⁺), exp 415 (MH⁺) Free base 99

N-(4-hydroxy-3- biphenylyl)-4- ({methyl[3-(methyl- amino)propyl]a-mino}methyl)benza- mide cal'd 404 (MH⁺), exp 404 (MH⁺) Free base 100

N-(4-hydroxy-3- biphenylyl)-4-[(4- methyl-1- piperazinyl)meth-yl]benzamide cal'd 402 (MH⁺), exp 402 (MH⁺) Free base 101

N-(4-hydroxy-3- biphenylyl)-4- ({methyl[2-(methyl- amino)ethyl]a-mino}methyl)benza- mide cal'd 390 (MH⁺), exp 390 (MH⁺) Free base 102

4-({[(1-ethyl-4- piperidinyl)methyl]a- mino}methyl)-N-(4- hydroxy-3-biphenylyl)benzamide cal'd 444 (MH⁺), exp 444 (MH⁺) Free base 103

N-(4-hydroxy-3- biphenylyl)-4- {[methyl(4- pyridinyl)amino]meth-yl}benzamide cal'd 410 (MH⁺), exp 410 (MH⁺) Free base 104

N-(4-hydroxy-3- biphenylyl)-4- ({methyl[2-(4- pyridinyl)ethyl]ami-no}methyl)benzamide cal'd 438 (MH⁺), exp 338 (MH⁺) Free base 105

N-(4-hydroxy-3- biphenylyl)-4-({[2-(3- pyridinyl)ethyl]ami-no}methyl)benzamide cal'd 424 (MH⁺), exp 424 (MH⁺) Free base 106

4-{[3- (dimethylamino)-1- pyrrolidinyl]methyl}- N-(4-hydroxy-3-biphenylyl)benzamide cal'd 416 (MH⁺), exp 416 (MH⁺) Free base 107

4-{[(2-aminoethyl)ami- no]methyl}-N-(4- hydroxy-3- biphenylyl)benzamidecal'd 362 (MH⁺), exp 362 (MH⁺) Free base 108

4-[(2,3-dihydro-1H- inden-2- ylamino)methyl]-N- (4-hydroxy-3-biphenylyl)benzamide cal'd 435 (MH⁺), exp 435 (MH⁺) Free base 109

N-(4-hydroxy-3- biphenylyl)-4-({[3-(4- pyridinyl)propyl]a-mino}methyl)benza- mide cal'd 438 (MH⁺), exp 438 (MH⁺) Free base 110

N-(4-hydroxy-3- biphenylyl)-4-({[(1- methyl-3- pyrrolidinyl)methyl]a-mino}methylbenza- mide cal'd 416 (MH⁺), exp 416 (MH⁺) Free base 111

N-(4-hydroxy-3- biphenylyl)-4-({[2- (1H-pyrazol-1- yl)ethyl]aminoimeth-yl)benzamide cal'd 413 (MH⁺), exp 413 (MH⁺) Free base 112

N-(4-hydroxy-3- biphenylyl)-4- {[methyl(tetrahydro- 3-furanyl)amino]meth- yl}benzamide cal'd 403 (MH⁺), exp 403 (MH⁺) Freebase 113

N-(4-hydroxy-3- biphenylyl)-4- {[methyl(2- pyrazinylmethyl)ami-no]methyl}benzamide cal'd 425 (MH⁺), exp 425 (MH⁺) Free base 114

N-(4-hydroxy-3- biphenylyl)-4- ({methyl[(1-methyl- 1H-pyrazol-4-yl)methyl]ami- no}methyl)benzamide cal'd 427 (MH⁺), exp 427 (MH⁺) Freebase 115

N-(4-hydroxy-3- biphenylyl)-4- ({methyl[(1-methyl- 4-piperidinyl)methyl]a- mino}methyl)benza- mide cal'd 444 (MH⁺), exp 444(MH⁺) Free base 116

N-(4-hydroxy-3- biphenylyl)-4-{[2-(2- pyridinyl)-1- pyrrolidinyl]meth-yl}benzamide cal'd 450 (MH⁺), exp 450 (MH⁺) Free base 117

N-(4-hydroxy-3- biphenylyl)-4-{[(3- methoxybenzyl)ami-no]methyl}benzamide cal'd 439 (MH⁺), exp 439 (MH⁺) Free base

H. Compounds Synthesized According to Scheme 8

1,1-dimethylethyl(3-{[(4-{[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}phenyl)carbonyl]amino}biphenyl-4-yl)carbamate

(4S)-4-phenyl-1,3-oxazolidin-2-one (0.158 g, 0.968 mmol) was added to astirred, 0° C. cooled mixture of sodium hydride (0.041 g, 1.014 mmol) inTHF (2 ml) and the mixture was stirred at 0° C. for 15 min.1,1-dimethylethyl 4-(bromomethyl)benzoate (0.25 g, 0.922 mmol) was thenadded and the reaction mixture was allowed to stirred at 0° C. for 30min. Saturated ammonium chloride was added and the mixture was extractedwith ethyl acetate (10 mL×2×). The combined organic fractions were driedover Na₂SO₄, filtered and the solvent was evaporated under reducedpressure to obtain 1,1-dimethylethyl4-{[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}benzoate. The esterwas taken to the next step without further purification.

TFA (1 ml, 12.98 mmol) was added to 1,1-dimethylethyl4-{[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}benzoate (0.35 g,0.990 mmol) in DCM (2 ml) and the mixture was stirred at roomtemperature for 3 h. The reaction mixture was then concentrated andcarried forward without further purification.

4-{[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}benzoic acid wasprepared according to the procedure described in section A for thepreparation of1,1-dimethylethyl[2-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]-4-(2-thienyl)phenyl]carbamate.MS: Card 586 (MNa⁺), exp (MNa⁺) 586.

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 8 Example # Structure Name MS Salt forms 118

N-(4-aminobiphenyl- 3-yl)-4-{[(4S)-2-oxo- 4-phenyl-1,3- oxazolidin-3-yl]mcthyl}benzamidce Cal'd 464 (MH⁺), exp (MH⁺) 464. Free base 119

N-(4-aminobiphenyl- 3-yl)-4-{[(4R)-2- oxo-4- (phenylmethy1)-1,3-oxazolidin-3- yl]methyl}benzamide Cal'd 478 (MH⁺), exp 478 (MH⁺) Freebase 120

N-[2-amino-5-(2- thienyl)phenyl]-4- {[(4R)-2-oxo-4- (phenylmethyl)-1,3-oxazolidin-3- yl]methyl}benzamide Cal'd 484 (MH⁺), exp 484 (MH⁺) Freebase 121

N-(4-aminobiphenyl- 3-yl)-4-{[(4S)-2-oxo- 4-(phenylmethyl)-1,3-oxazolidin-3- yl]methyl}benzamide Cal'd 478 (MH⁺), exp 478 (MH⁺)Free base 122

N-(4-aminobiphenyl- 3-yl)-4-{[(4R)-2- oxo-4-phenyl-1,3-oxazolidin-3-yl]meth- yl}benzamide Cal'd 464 (MH⁺), exp (MH⁺) 464. Freebase

I. Compounds Synthesized According to Scheme 9

{1-[(Trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methanol

A solution of ethyl1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole-4-carboxylate (1.00 g, 4.40mmol) and THF (14.6 mL) was cooled to 0° C. and a solution of LAH (4.40mL, 1M in THF) was added dropwise. The mixture was stirred for 1 h, andthe cold bath was removed and stirred for an additional hour. Thereaction was cooled to 0° C. and a solution of saturated sodium sulfate(4.4 mL) was added. The mixture was warmed to room temperature, stirred30 min, and filtered. The filtrate was concentrated and the residueazeotroped with ethanol to afford a colorless oil purified via MPLC, 40Mcolumn, 1-8% MeOH in DCM afforded the title material as a clear,colorless oil. MS: cal'd 186 (MH⁺), exp 186 (MH⁺).

Methyl 4-({[(2,4-dinitrophenyl)sulfonyl]amino}methyl)benzoate

A solution of methyl 4-(aminomethyl)benzoate (1.00 g, 4.96 mmol),2,4-dinitrobenzenesulfonyl chloride (1.39 g, 5.21 mmol), DCM (16.5 mL)and pyridine (481 uL, 5.95 mmol) was treated with Hunig's base (2.17 mL,12.4 mmol) and stirred for 2 h. The reaction was concentrated, takeninto EtOAc and washed with 2M aq. HCl 2×, water, brine, dried (MgSO₄)and concentrated to afford a brown oil used crude in the next reaction.MS: cal'd 396 (MH⁺), exp 396 (MH⁺).

Methyl4-{[[(2,4-dinitrophenyl)sulfonyl]({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate

A solution of {1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methanol(241 mg, 1.30 mmol), methyl4-({[(2,4-dinitrophenyl)sulfonyl]amino}methyl)benzoate (514 mg, 1.30mmol), triphenylphosphine (409 mg, 1.56 mmol) and benzene (4.34 mL) wastreated with diethylazodicarboxylate (247 uL, 1.56 mmol). After one houradditional portions of triphenylphosphine (204 mg, 0.780 mmol) anddiethylazodicarboxylate (124 uL, 0.780 mmol) The reaction was dilutedwith EtOAc and washed with 2M aq. HCl 2×, water, brine, dried (MgSO₄)and concentrated to afford a brown oil used crude in the next reaction.MS: cal'd 563 (MH⁺), exp 563 (MH⁺).

Methyl4-{[({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate

Crude methyl4-{[[(2,4-dinitrophenyl)sulfonyl]({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate(732 mg, 1.30 mmol) was dissolved in propylamine (2.25 mL) and stirredovernight. The reaction was concentrated and purified via MPLC, 1-8%MeOH in DCM to afford the requisite product as a clear, colorless oil.MS: cal'd 333 (MH⁺), exp 333 (MH⁺).

Methyl4-{[acetyl({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate

A solution of methyl4-{[({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate(133 mg, 400 mmol), DCM (1.33 mL) and Et₃N (167 uL, 1.2 mmol) weretreated with acetyl chloride (42.7 uL, 0.600 mmol) and stirred for 5min. The reaction was diluted with EtOAc and washed with 2M aq. HCl,water, brine, dried (MgSO₄) and concentrated to afford the requisitecompound as a clear, colorless residue. MS: cal'd 375 (MH⁺), exp 375(MH⁺).

4-({Acetyl[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)benzoicacid

A solution of methyl4-{[acetyl({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate(101 mg, 0.270 mmol), THF (809 uL) and MeOH (270 uL) was treated withaqueous LiOH (270 uL, 0.809 mmol, 3M in water). The reaction immediatelyturned red and was stirred overnight. The reaction was quenched with 2Maq. HCl and extracted with EtOAc 2×. The combined organic layers werewashed with brine, dried (MgSO₄) and concentrated to afford theprotosilylated carboxylic acid as a yellow oil. MS: cal'd 361 (MH⁺), exp361 (MH⁺).

Example 1234-({Acetyl[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)-N-[2-amino-5-(2-thienyl)phenyl]benzamide

4-({Acetyl[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)benzoicacid (17.7 mg, 0.061 mmol),1,1-dimethylethyl[2-({[4-(chloromethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate(22 mg, 0.074 mmol), HOBT (11 mg, 0.074 mmol) and EDC (12 mg, 0.074mmol) were taken into DMF (409 ul) and stirred at 60° C. overnight. Thereaction was diluted with EtOAc and washed with ½ saturated NaHCO₃ 3×,brine, dried (MgSO₄) and concentrated to afford a residue taken into ca1 mL DCM:TFA (2:1) and stirred for 2 h. This solution was concentratedand purified via HPLC (20-100% MeCN in water with 0.025% TFA) to affordfractions poured into sat. aq. NaHCO₃ and extracted with EtOAc 2×. Thecombined organic layers were washed with brine, dried (MgSO₄) andconcentrated to afford the requisite material as a dark tan solid. ¹HNMR (d6-DMSO, 600 MHz, 90° C.) δ 9.46 (br s, 1H), 8.00-7.90 (m, 3H),7.50 (d, J=2.1 Hz, 1H), 7.32 (d, J=8.2 Hz, 2H), 7.29 (dd, J=5.3, 1.2 Hz,1H), 7.24 (dd, J=8.5, 2.3 Hz, 1H), 7.17 (dd, J=3.5, 1.2 Hz, 1H), 7.01(dd, J=5.0, 3.5 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 4.94 (br s, 2H),4.66-4.54 (m, 3H), 4.50 (s, 2H), 3.98 (s, 2H), 2.24-2.00 (m, 3H). MS:cal'd 461 (MH⁺), exp 461 (MH⁺).

J. Compounds Synthesized According to Scheme 10

Methyl 4{[tert-butoxycarbonyl)(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate

N-(tert-oxycarbonyl)glycine (1.0063 g, 4.35 mmol) was dissolved in THF(10 ml). The solution was cooled to −78° C. Lithiumbis(trimethylsilyl)amide (6.5 ml, 6.48 mmol) was added. The reaction wasallowed to stir for approximately 30 minutes. Methyl4-(bromomethyl)benzoate (0.99 mg, 4.32 mmol) was added. The reaction wasallowed to stir overnight, slowly warming to room temperature. Thereaction was diluted with ethyl acetate and quenched with saturatedaqueous ammonium chloride. The aqueous layer was extracted three timeswith ethyl acetate. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated. The resulting residue was purifiedby column chromatography. MS: cal'd 402 (M+23), exp 402 (M+23).

4-{[(tert-butoxycarbonyl) (2-tert-butoxy-2-oxoethyl)amino]methyl}benzoicacid

Methyl 4 {[tert-butoxycarbonyl)(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (0.95 g, 2.5 mmol) wasdissolved in THF (25 ml). Potassium trimethylsilanolate (0.65 g, 5 mmol)was added. The reaction was allowed to stir overnight at roomtemperature. Reaction was not complete, but was quenched anyway.Hydrochloric acid (5 ml, 1N) was added to the reaction and allowed tostir. The reaction was diluted with ethyl acetate and washed with brine.The aqueous layer was extracted three times with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated. The resulting residue was dissolved in THF (25 ml).Potassium trimethylsilanolate (0.65 g, 5 mmol) was added. The reactionwas allowed to stir overnight at room temperature. Hydrochloric acid (5ml, 1N) was added to the reaction and allowed to stir. The reaction wasdiluted with ethyl acetate and washed with brine. The aqueous layer wasextracted three times with ethyl acetate. The combined organic layerswere dried over sodium sulfate, filtered, and concentrated. Theresulting material was purified by HPLC. MS: cal'd 388 (M+23), exp 388(M+23).

Additional analogs were prepared in procedures similar to thosedescribed for the preparation of the above.

TABLE 10 Example # Structure Name MS Salt forms 124

{[4-({[2-amino-5-(2- thienyl)phenyl]ami- no}carbonyl)benzyl]a-mino}acetic acid cal'd 382 (MH⁺), exp 382 (MH⁺) TFA salt 125

{[4-({[2-amino-5-(3- thienyl)phenyl]ami- no}carbonyl)benzyl]a-mino}acetic acid cal'd 382 (MH⁺), exp 382 (MH⁺) TFA salt

The compounds in the above examples exhibit histone deacetylaseinhibitory activity and proliferation inhibitory activity as shown inTable 11.

TABLE 11 HDAC1 IP* Prol-72 hr IP* Example # (nM) (μM) 1 16 0.38 2 81nd{circumflex over ( )} 3 17 nd{circumflex over ( )} 4 5.8 0.37 5 20nd{circumflex over ( )} 6 16 1.0 7 70 nd{circumflex over ( )} 8 28nd{circumflex over ( )} 9 17 0.26 10 16 0.23 11 nd{circumflex over ( )}0.13 12 29 0.36 13 45 0.39 14 320 1.4 15 58 0.82 16 12 0.13 17 6.0 0.09618 19 0.12 19 19 0.11 20 31 0.30 21 77 0.64 22 53 0.32 23 18 0.32 24 170.12 25 17 0.22 26 15 0.17 27 10 0.15 28 25 0.26 29 14 0.21 30 23 0.2231 14 0.42 32 42 0.34 33 21 0.20 34 72 0.31 35 19 0.16 36 11 0.12 37 120.13 38 12 0.15 39 15 0.096 40 16 0.15 41 16 0.17 42 15 0.12 43 11 0.1344 24 0.20 45 34 0.19 46 20 0.14 47 16 0.15 48 13 0.11 49 10 0.17 50 190.30 51 140 2.1 52 15 0.25 53 16 0.34 54 12 0.16 55 18 0.16 56 13 0.1657 18 0.28 58 24 0.38 59 20 0.44 60 17 0.26 61 10 1.7 62 10 3.6 63 130.67 64 18 0.54 65 35 0.9 66 23 1.1 67 23 2.1 68 27 9.1 69 15 9.7 70 18013 71 970 nd{circumflex over ( )} 72 1800 nd{circumflex over ( )} 73 110nd{circumflex over ( )} 74 690 nd{circumflex over ( )} 75 76nd{circumflex over ( )} 76 89 nd{circumflex over ( )} 77 150nd{circumflex over ( )} 78 72 nd{circumflex over ( )} 79 2500nd{circumflex over ( )} 80 120 nd{circumflex over ( )} 81 32nd{circumflex over ( )} 82 91 nd{circumflex over ( )} 83 65nd{circumflex over ( )} 84 9.9 nd{circumflex over ( )} 85 48nd{circumflex over ( )} 86 95 nd{circumflex over ( )} 87 220nd{circumflex over ( )} 88 350 nd{circumflex over ( )} 89 450nd{circumflex over ( )} 90 250 nd{circumflex over ( )} 91 44nd{circumflex over ( )} 92 100 nd{circumflex over ( )} 93 340nd{circumflex over ( )} 94 31 nd{circumflex over ( )} 95 27000nd{circumflex over ( )} 96 360 nd{circumflex over ( )} 97 260nd{circumflex over ( )} 98 2100 nd{circumflex over ( )} 99 18nd{circumflex over ( )} 100 2400 nd{circumflex over ( )} 101 35nd{circumflex over ( )} 102 65 nd{circumflex over ( )} 103 13nd{circumflex over ( )} 104 33 nd{circumflex over ( )} 105 2500nd{circumflex over ( )} 106 50 nd{circumflex over ( )} 107 72nd{circumflex over ( )} 108 160 nd{circumflex over ( )} 109 100nd{circumflex over ( )} 110 180 nd{circumflex over ( )} 111 33nd{circumflex over ( )} 112 43 nd{circumflex over ( )} 113 31nd{circumflex over ( )} 114 24 nd{circumflex over ( )} 115 78nd{circumflex over ( )} 116 280 nd{circumflex over ( )} 117 4300nd{circumflex over ( )} 118 64 1.4 119 89 1.7 120 84 0.92 121 96 1.4 12258 1.1 123 9.5 0.087 124 34 >20000 125 42 >20000 *IP = inflection point{circumflex over ( )}nd = not determined

Example 2 HDAC Inhibition by Novel Compounds HDAC1-Flag Assay:

Novel compounds were tested for their ability to inhibit histonedeacetylase, subtype 1 (HDAC1) using an in vitro deacetylation assay.The enzyme source for this assay was an epitope-tagged human HDAC1complex immuno-purified from stably expressing mammalian cells. Thesubstrate consisted of a commercial product containing an acetylatedlysine side chain (BIOMOL Research Laboratories, Inc., Plymouth Meeting,Pa.). Upon deacetylation of the substrate by incubation with thepurified HDAC1 complex, a fluorophore is produced that is directlyproportional to the level of deacetylation. Using a substrateconcentration at the Km for the enzyme preparation, the deacetylationassay was performed in the presence of increasing concentrations ofnovel compounds to semi-quantitatively determine the concentration ofcompound required for 50% inhibition (IC50) of the deacetylationreaction.

Example 3 HDAC Inhibition in Cell Lines ATP Assay

The novel compounds of the present invention were tested for theirability to inhibit proliferation of the human cervical cancer (HeLa) andcolon carcinoma (HCT116) cells.

In this assay, also referred to as the Vialight Assay, cellular ATPlevels are measured as a means of quantifying cellular proliferation.This assay makes use of a bioluminescent method from Cambrex (ViaLightPLUS, cat. #LT07-121). In the presence of ATP, luciferase convertsluciferin to oxyluciferin and light. The amount of light produced(emission at 565 nM) is measured and correlates with a relative amountof proliferation. Human cervical cancer (HeLa) or colon carcinoma(HCT116) cells were incubated with vehicle or increasing concentrationsof compound for 48, 72 or 96 hours. Cell proliferation was quantified byadding the cell lysis reagent (provided in the Vialight assay kit)directly to culture wells, followed by addition of the ATP-monitoringreagent (containing luciferase/luciferin). The amount of light producedis then measured (emission at 565 nM). The quantity of light produced,as measured by 565 nM absorbance, is directly proportional to the numberof living cells in culture.

Example 4 Pharmacology Profiles

The ancillary pharmacology profiles of the SHI-1:2 carbamate analogswere also gathered to investigate off-target activities (Table 12). CYPinhibition potential was determined against a number of human isoforms,and ion channel inhibition in a displacement binding assay usingradio-labeled MK-499.13 SHI-1:2 2a was found to be an inhibitor of CYPisoforms and it exhibits IKr ion channel binding activity (IC50 3.0 μM).The CYP inhibition for 2a was greatest for CYP3A4 with 70% @ 1 μM. BothCYP2D6 and CYP2C9 were also affected but to a lesser extent, 69 and 71%@ 10 μM, respectively. The 3-pyridyl amide 14a faired better than theparent with respect to both IKr binding, as well as, CYP inhibition. For2-pyridyl analog 14a, the IKr binding and CYP3A4 inhibition was alsoattenuated. The benzyl and phenyl analogs, 14c and 14d, respectively,did not appreciably inhibit CYP enzymes or IKr binding. Based on theseresults, additional analogs were explored to maintain the cleanoff-target activity, but improve biochemical and anti-proliferationactivities of the initial carbamate analogs.

Based on the off-target activity issues noted with the 3-pyridylmethylcarbamate, additional analogs were explored focusing on alkylsubstituents. Accordingly, the ethyl and methyl carbamate analogues of2a were prepared, affording 14e and 14f, respectively, which maintainpotent enzymatic and cellular activity (Table 13). Gratifyingly, CYPinhibition and IKr ion channel binding activities were greatlyattenuated. The desired trend of reduced off-target activity continuedwith amide analogues 14g and 14h. The HDAC1 enzymatic inhibitoryactivities for 14g and 14h were IC₅₀=10 nM for both analogs and theanti-proliferation activities were GI₅₀=220 and 150 nM, respectively,indicating tolerance for various moieties in the recognition domain.Larger alkyl groups are acceptable in the recognition domain. Cyclohexylamide 14i, for example, has slightly reduced enzyme andanti-proliferative activities with minimal off-target activity.

TABLE 12 The initial series of biaryl SHI-1:2

HCT- % MK-499 HDAC1 116 Binding % CYP Inhibition @ IC₅₀ GI₅₀ Inhibition@ 10 μM R (nM)^(a) (nM)^(a) 10 μM 3A4 2C9 2D6  2a 3-pyridyl- 10 225 IC₅₀= 3.0 μM 70 @ 69 71 CH₂O 1 μM 14a 3-pyridyl- 11 337 IC₅₀ = 3.7 μM 65 7325 (CH₂)₂ 14b 2-pyridyl- 8 435 51 38 67 29 CH₂O 14c BnO 17 820 30 28 2716 14d PhO 16 1440 15 22 21 12 ^(a)Values are means of n ≧ 2experiments.

TABLE 13 The alkyl carbamate and amide series of biaryl SHI-1:2.

HCT- % MK-499 HDAC1 116 Binding % CYP Inhibition @ IC₅₀ GI₅₀ Inhibition@ 10 μM R (nM)^(a) (nM)^(a) 10 μM 3A4 2C9 2D6  2 3-pyridyl- 10 225 IC₅₀= 3.0 μM 70 @ 69 71 CH₂O 1 μM 14e EtO 13 230 40 22 35 26 14f MeO 10 23028 23 46 49 14g nPr 10 220 38 33 27 28 14h Et 10 150 24 30 28 38 14iCyclohexyl- 20 335 30 12 32 17 ^(a)Values are means of n ≧ 2experiments.

While this invention has been particularly shown and described withreferences to embodiments thereof, it will be understood by thoseskilled in the art that various changes in form and details may be madetherein without departing from the meaning of the invention described.Rather, the scope of the invention is defined by the claims that follow.

1. A compound represented by the following structural Formula:

wherein Cy is

R¹ and R² are independently H, OH, halo, NH₂, C₁-C₄ alkyl, C₁-C₄alkenyl, C₁-C₄ alkynyl, C₁-C₄ alkoxy, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocyclic or substituted or unsubstituted aryl; R³ isindependently H, OH, NH₂, nitro, CN, amide, carboxyl, C₁-C₇ alkoxy,C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇ haloalkyloxy, C₁-C₇ hydroxyalkyl,C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—, C₁-C₇ alkyl-C(═O)—, C₁-C₇ alkynyl,halo, hydroxyalkoxy, C₁-C₇ alkyl-NHSO₂—, C₁-C₇ alkyl-SO₂NH—, C₁-C₇alkylsulfonyl, C₁-C₇ alkylamino or di(C₁-C₇)alkylamino; R⁴ is selectedfrom —NR⁶R⁷, and

R⁵ is independently H, OH, NH₂, nitro, CN, amide, carboxyl, C₁-C₇alkoxy, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇ haloalkyloxy, C₁-C₇hydroxyalkyl, C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—, C₁-C₇ alkyl-C(═O)—,C₁-C₇ alkynyl, halo, hydroxyalkoxy, C₁-C₇ alkyl-NHSO₂—, C₁-C₇alkyl-SO₂NH—, C₁-C₇ alkylsulfonyl, C₁-C₇ alkylamino ordi(C₁-C₇)alkylamino; R⁶ is independently H, C₁-C₄ alkyl or C(O)R⁹; R⁷ isselected from H, —(CR^(a) ₂)_(s)C(O)(CR^(a) ₂)_(q)R¹³, —(CR^(a)₂)_(s)C(O)O(CR^(a) ₂)_(q)R¹², —(CR^(a) ₂)_(s)C(O)NR¹¹, —(CR^(a)₂)_(q)R¹⁰, —(CR^(a) ₂)_(s)SO₂NR¹¹, and —(CR^(a) ₂)_(v)NR¹¹; R⁸ isindependently H, C₁-C₄ alkyl, N(R⁶)₂, —(CR^(a) ₂)_(q)R¹² or when m is atleast 2, two adjacent R⁸ form an aryl ring; R⁹ is H or C₁-C₄ alkyl; R¹⁰is H, substituted or unsubstituted C₃-C₈ cycloalkyl, pyrimidinyl,substituted pyridyl, substituted or unsubstituted thienyl, substitutedor unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, orphenyl; R¹¹ is independently H, substituted or unsubstituted C₁-C₇alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclic, substituted or unsubstituted heteroaryl orsubstituted or unsubstituted aryl, substituted or unsubstituted C₃-C₈alkylcycloalkyl, substituted or unsubstituted alkylheterocyclic,substituted or unsubstituted alkylheteroaryl or substituted orunsubstituted alkylaryl; R¹² is independently H, unsubstituted C₁-C₇alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclic orsubstituted or unsubstituted aryl; R¹³ is H, substituted orunsubstituted C₁-C₇ alkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocyclic or unsubstituted aryl; R¹⁷ and R²¹ areindependently hydrogen or fluoro; R¹⁸, R¹⁹ or R²⁰ are independentlyhydrogen, halo, methyl, methoxy or halomethyl; R²², R²³ and R²⁴ areindependently hydrogen, methyl, amino, hydroxyl or halo; R^(a) isindependently H or C₁-C₄ alkyl; Ring B is aryl or heteroaryl; m is 1, 2,3, 4, 5, 6, 7, 8, 9 or 10; p is 1, 2, 3 or 4; s and q are independently0, 1, 2, 3, or 4; t and v are independently 1, 2, 3 or 4; L¹ is(CH₂)_(r), ethenyl or cyclopropyl, wherein r is 0, 1 or 2; X is OH, SHor NH₂; With the proviso that when R⁵ is H, X is NH₂ or OH, L¹ is abond, R³ is H, R¹ and R² are H, R⁴ is

and Ring B is phenyl, then Cy is not

or a stereoisomer or pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, R¹ and R² are independently H, OH, halo, NH₂, C₁-C₄alkyl, or C₁-C₁₀ alkoxy; R³ is independently H, OH, NH₂, nitro, CN,amide, carboxyl, C₁-C₇ alkoxy, C₁-C₇ alkyl, C₁-C₇ haloalkyl, C₁-C₇haloalkyloxy, C₁-C₇ hydroxyalkyl, C₁-C₇ alkenyl, C₁-C₇ alkyl-C(═O)O—,C₁-C₇ alkyl-C(═O)—, C₁-C₇ alkynyl, halo, hydroxyalkoxy, C₁-C₇alkyl-NHSO₂—, C₁-C₇ alkyl-SO₂NH—, C₁-C₇ alkylsulfonyl, C₁-C₇ alkylaminoor di(C₁-C₇)alkylamino; R⁴ is selected from —NR⁶R⁷, and

R⁵ is independently H, OH, NH₂, nitro, CN, amide, carboxyl, C₁-C₂alkoxy, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ haloalkyloxy, C₁-C₂hydroxyalkyl, C₁-C₂ alkenyl, C₁-C₂ alkyl-C(═O)O—, C₁-C₂ alkyl-C(═O)—,C₁-C₂ alkynyl, halo, hydroxyalkoxy, C₁-C₂ alkyl-NHSO₂—, C₁-C₂alkyl-SO₂NH—, C₁-C₂ alkylsulfonyl, C₁-C₂ alkylamino ordi(C₁-C₂)alkylamino; R⁶ is independently H or C₁-C₄ alkyl; R⁷ is H,—C(O)(CR^(a) ₂)_(q)R¹³, —(CR^(a) ₂)_(s)C(O)NR¹¹ or —(CR^(a) ₂)_(v)NR¹¹;R⁸ is independently H, C₁-C₄ alkyl, N(R⁶)₂, —(CR^(a) ₂)_(q)R¹² or when mis at least 2, two adjacent R⁸ form an aryl ring; R⁹ is H or C₁-C₄alkyl; R¹¹ is independently H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,heteroaryl, aryl, heterocyclic, C₃-C₆ alkylcycloalkyl, alkylheteroaryl,alkylaryl or alkylheterocyclic, wherein the alkyl, cycloalkyl,heteroaryl, heterocyclic, aryl, alkylcycloalkyl, alkylheteroaryl,alkylheterocyclic, or alkylaryl is optionally substituted with aryl,heteroaryl, halo, C₁-C₄ alkyl, N(R⁶)₂, OH, C₁-C₄ alkoxy or C₁-C₄haloalkyl; R¹² is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, heteroaryl, aryl orheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclic oraryl is optionally substituted with aryl, heteroaryl, halo, C₁-C₄ alkyl,N(R⁶)₂, OH, C₁-C₄ alkoxy or C₁-C₄ haloalkyl; R¹³ is H, C₂-C₇ alkyl,C₃-C₈ cycloalkyl, heteroaryl, or aryl, wherein the cycloalkyl,heteroaryl or aryl is optionally substituted with aryl, heteroaryl,halo, C₁-C₄ alkyl, N(R⁶)₂, OH, C₁-C₄ alkoxy or C₁-C₄ haloalkyl; R^(a) isindependently H or C₁-C₄ alkyl; Ring B is aryl or heteroaryl; m is 1, 2,3, 4, 5, 6, 7, or 8; p is 1, 2, 3 or 4; s and q are independently 0, 1,2, 3, or 4; t and v are independently 1, 2, 3 or 4; L¹ is (CH₂)_(r),ethenyl or cyclopropyl, wherein r is 0, 1 or 2; X is OH or NH₂; or astereoisomer or pharmaceutically acceptable salt thereof.
 3. Thecompound of claim 1, wherein R¹ and R² are H; R³ is H; R⁴ is —NR⁶R⁷; R⁵is H; R⁶ is H or C₁-C₄ alkyl; R⁷ is —C(O)O(CR^(a) ₂)_(q)R¹²; R¹² is H,C₁-C₄ alkyl, cycloalkyl, aryl, or heteroaryl; R^(a) is independently Hor C₁-C₄ alkyl; Ring B is aryl or heteroaryl; p is 1, 2, 3, or 4; t is1, 2, 3 or 4; q is independently 0, 1 or 2; L¹ is a bond; X is NH₂; or astereoisomer or pharmaceutically acceptable salt thereof.
 4. Thecompound of claim 3, wherein R¹² is C₁-C₄ alkyl, and all othersubstituents are defined in claim
 3. 5. The compound of claim 3, whereinR¹² is pyridin-2-yl, and all other substituents are defined in claim 3.6. The compound of claim 3, wherein Cy is phenyl, and all othersubstituents are defined in claim
 3. 7. The compound of claim 4, whereinRing B is


8. The compound of claim 4, wherein Cy is

and all other substituents are defined in claim
 4. 9. A compoundselected from:pyridin-3-ylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;methyl4′-amino-3′-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]biphenyl-4-carboxylate;pyridin-3-ylmethyl[(4-{[(2-amino-5-pyridin-3-ylphenyl)amino]carbonyl}phenyl)methyl]carbamate;pyridin-3-ylmethyl{[4-({[2-amino-5-(3-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;pyridin-3-ylmethyl[(4-{[(4-hydroxybiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;pyridin-3-ylmethyl[(4-{[(2-hydroxy-5-pyridin-3-ylphenyl)amino]carbonyl}phenyl)methyl]carbamate;1,1-dimethylethyl[(4-{[(4-hydroxybiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;4-(aminomethyl)-N-(4-hydroxybiphenyl-3-yl)benzamide;methyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;ethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;1-methylethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;propyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;2-methylpropyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;phenyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;phenylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;ethyl{[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;methyl{[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;1-methylethyl{[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;propyl{[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;2-methylpropyl{[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;phenyl{[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;phenylmethyl{[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}carbamate;4-[(acetylamino)methyl]-N-(4-aminobiphenyl-3-yl)benzamide;N-(4-aminobiphenyl-3-yl)-4-[(propanoylamino)methyl]benzamide;N-(4-aminobiphenyl-3-yl)-4-[(butanoylamino)methyl]benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(cyclopropylcarbonyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(2-methylpropanoyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(3-methylbutanoyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(cyclobutylcarbonyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(3-phenylpropanoyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(cyclohexylcarbonyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(cyclopentylcarbonyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(phenylacetyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(phenylcarbonyl)amino]methyl}benzamide;4-[(acetylamino)methyl]-N-[2-amino-5-(2-thienyl)phenyl]benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-[(propanoylamino)methyl]benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-[(butanoylamino)methyl]benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(cyclopropylcarbonyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(2-methylpropanoyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(3-methylbutanoyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(cyclobutylcarbonyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(3-phenylpropanoyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(cyclohexylcarbonyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(cyclopentylcarbonyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(phenylacetyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(phenylcarbonyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(pyridin-2-ylacetyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(pyridin-3-ylacetyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(pyridin-4-ylacetyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(3-pyridin-3-ylpropanoyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(pyridin-2-ylacetyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(pyridin-4-ylacetyl)amino]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(3-pyridin-3-ylpropanoyl)amino]methyl}benzamide;(2S)—N-[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]pyrrolidine-2-carboxamide;(2S)—N-(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}benzyl)pyrrolidine-2-carboxamide;pyridin-2-ylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate;N-[2-amino-5-(2-thienyl)phenyl]-4-({[(dimethylamino)sulfonyl]amino}methyl)benzamide;N-(4-amino-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide;N-(4-amino-3-biphenylyl)-4-{[methyl(4-pyridinyl)amino]methyl}benzamide;N-(4-amino-3-biphenylyl)-4-({[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]amino}methyl)benzamide;N-(4-amino-3-biphenylyl)-4-({methyl[3-(methylamino)propyl]amino}methyl)benzamide;N-(4-amino-3-biphenylyl)-4-[(isobutylamino)methyl]benzamide;N-(4-amino-3-biphenylyl)-4-{[(2-methoxy-1-methylethyl)amino]methyl}benzamide;N-(4-amino-2′-fluoro-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide;N-(4-amino-3′-fluoro-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide;N-[2-amino-5-(4-methyl-2-thienyl)phenyl]-4-[(4-pyridinylamino)methyl]benzamide;N-[2-amino-5-(4-methyl-3-thienyl)phenyl]-4-[(4-pyridinylamino)methyl]benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[(2-phenylethyl)amino]methyl}benzamide;4-({[2-(4-bromophenyl)ethyl]amino}methyl)-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-[(isobutylamino)methyl]benzamide;N-(4-hydroxy-3-biphenylyl)-4-({[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methyl]amino}methyl)benzamide;4-[(cyclopropylamino)methyl]-N-(4-hydroxy-3-biphenylyl)benzamide;4-(anilinomethyl)-N-(4-hydroxy-3-biphenylyl)benzamide;4-[(cyclopentylamino)methyl]-N-(4-hydroxy-3-biphenylyl)benzamide;4-{[(cyclopropylmethyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)benzamide;4-({[2-(dimethylamino)ethyl]amino}methyl)-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[(3-pyridinylmethyl)amino]methyl}benzamide;N-(4-hydroxy-3-biphenylyl)-4-({[3-(1-pyrrolidinyl)propyl]amino}methyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-(1-piperazinylmethyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-[(4-pyridinylamino)methyl]benzamide;N-(4-hydroxy-3-biphenylyl)-4-(4-morpholinylmethyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[(3-isopropoxypropyl)amino]methyl}benzamide;N-(4-hydroxy-3-biphenylyl)-4-[(4-methyl-1-piperidinyl)methyl]benzamide;4-{[benzyl(methyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[(3-phenylpropyl)amino]methyl}benzamide;4-(3,4-dihydro-2(1H)-isoquinolinylmethyl)-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-({[2-(isopropylamino)ethyl]amino}methyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[(3-methylbutyl)amino]methyl}benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[methyl(2-phenylethyl)amino]methyl}benzamide;4-{[ethyl(methyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;4-(1,3-dihydro-2H-isoindol-2-ylmethyl)-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[(2-phenoxyethyl)amino]methyl}benzamide;4-{[(2-anilinoethyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[(2-thienylmethyl)amino]methyl}benzamide;N-(4-hydroxy-3-biphenylyl)-4-({methyl[3-(methylamino)propyl]amino}methyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-[(4-methyl-1-piperazinyl)methyl]benzamide;N-(4-hydroxy-3-biphenylyl)-4-({methyl[2-(methylamino)ethyl]amino}methyl)benzamide;4-({[(1-ethyl-4-piperidinyl)methyl]amino}methyl)-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[methyl(4-pyridinyl)amino]methyl}benzamide;N-(4-hydroxy-3-biphenylyl)-4-({methyl[2-(4-pyridinyl)ethyl]amino}methyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-({[2-(3-pyridinyl)ethyl]amino}methyl)benzamide;4-{[3-(dimethylamino)-1-pyrrolidinyl]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;4-{[(2-aminoethyl)amino]methyl}-N-(4-hydroxy-3-biphenylyl)benzamide;4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-N-(4-hydroxy-3-biphenylyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-({[3-(4-pyridinyl)propyl]amino}methyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-({[(1-methyl-3-pyrrolidinyl)methyl]amino}methylbenzamide;N-(4-hydroxy-3-biphenylyl)-4-({[2-(1H-pyrazol-1-yl)ethyl]amino}methyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[methyl(tetrahydro-3-furanyl)amino]methyl}benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[methyl(2-pyrazinylmethyl)amino]methyl}benzamide;N-(4-hydroxy-3-biphenylyl)-4-({methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino}methyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-({methyl[(1-methyl-4-piperidinyl)methyl]amino}methyl)benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[2-(2-pyridinyl)-1-pyrrolidinyl]methyl}benzamide;N-(4-hydroxy-3-biphenylyl)-4-{[(3-methoxybenzyl)amino]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]methyl}benzamide;N-[2-amino-5-(2-thienyl)phenyl]-4-{[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]methyl}benzamide;N-(4-aminobiphenyl-3-yl)-4-{[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]methyl}benzamide;{[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]amino}aceticacid;{[4-({[2-amino-5-(3-thienyl)phenyl]amino}carbonyl)benzyl]amino}aceticacid; and4-({Acetyl[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)-N-[2-amino-5-(2-thienyl)phenyl]benzamide;or a stereoisomer or pharmaceutically acceptable salt thereof.
 10. Apharmaceutical composition comprising a pharmaceutically effectiveamount of the compound according to claim 1, and a pharmaceuticallyacceptable carrier.
 11. A method for the treatment or prevention ofcancer in a mammal comprising the step of administering to the mammal atherapeutically effective amount of the compound of claim
 1. 12. Thecompound of claim 9 that is

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim9 that is

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim9 that is

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim9 that is

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim9 that is

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim9 that is

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim9 that is

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim9 that is

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim9 that is

or a pharmaceutically acceptable salt thereof.